Nanoparticle-based therapeutic strategies for chronic liver diseases: Advances and insights

Sathiyamoorthy Padmanaban; Ji-Won Baek; Sai Sahithya Chamarthy; Saipriya Chandrasekaran; Antony V Samrot; Vijayakumar Gosu; In-Kyu Park; Kamalakannan Radhakrishnan; Don-Kyu Kim

doi:10.1016/j.livres.2025.04.002

Liver Research ›› 2025, Vol. 9 ›› Issue (2) :104 -117. DOI: 10.1016/j.livres.2025.04.002

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Nanoparticle-based therapeutic strategies for chronic liver diseases: Advances and insights

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^a Department of Biomedical Sciences and BioMedical Sciences Graduate Program (BMSGP), Chonnam National University Medical School, Gwangju, Republic of Korea

^b Host-directed Antiviral Research Center, Department of Integrative Food, Bioscience and Biotechnology (BK21 FOUR), Chonnam National University, Gwangju, Republic of Korea

^c Department of Obstetrics, Gynecology, and Reproductive Sciences, Sanford Consortium for Regenerative Medicine, University of California San Diego (UCSD), San Diego, CA, USA

^d Department of Neuroscience, University of California San Diego (UCSD), San Diego, CA, USA

^e Department of Microbiology, Faculty of Medicine, Manipal University College Malaysia, Melaka, Malaysia

^f Department of Animal Biotechnology, Jeonbuk National University, Jeonju, Republic of Korea

^g Host-directed Antiviral Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea

^* E-mail addresses: pik96@jnu.ac.kr (In-Kyu Park)

^** E-mail addresses: Kamalakannan_2016@jnu.ac.kr (Kamalakannan Radhakrishnan)

^*** E-mail addresses: dkkim2@jnu.ac.kr (Don-Kyu Kim)

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Abstract

The liver is pivotal in protein synthesis, glucose and lipid metabolism, and detoxification. However, the liver is susceptible to both acute and chronic disorders, with chronic conditions being fatal. Chronic liver diseases (CLDs), such as liver fibrosis, which usually represents the early manifestation of cirrhosis, primarily result from hepatitis B and C viruses infections, metabolic disorders, alcohol abuse, immune-mediated attacks, and cholestatic injury. The progression of liver fibrosis contributes to the development of cirrhosis, which can further lead to hepatocellular carcinoma, portal hypertension, hepatic decompensation, and hepatic encephalopathy. The extracellular matrix deposition over time leading the hepatocyte necrosis (cirrhosis) is the main structural feature of CLDs and may cause hepatic failure. Certain conditions, such as hepatitis and autoimmune diseases, may promote the rapid deterioration of liver function. Acute and chronic liver failure causes may vary, with early referral for liver transplantation improving the chance of recovery. The healthcare system need improvements to manage patients with non-alcoholic fatty liver disease and alcoholic fatty liver disease, as they have the potential to progress to cirrhosis. Both conditions involve the release of reactive oxygen species and damage-associated molecular patterns from cytokines, hepatic stellate cells, and hepatocyte autophagy, leading to prolonged inflammation. While various medications target fibrosis and liver damage, nanoparticle-based drug delivery systems offer additional promise by promoting faster liver regeneration. This review provides a comprehensive overview of the potential of nanoparticle systems as a future therapeutic approach for treating liver disorders.

Keywords

Chronic liver diseases (CLDs) / Reactive oxygen species (ROS) / Antioxidants / Nanoparticles

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Sathiyamoorthy Padmanaban, Ji-Won Baek, Sai Sahithya Chamarthy, Saipriya Chandrasekaran, Antony V Samrot, Vijayakumar Gosu, In-Kyu Park, Kamalakannan Radhakrishnan, Don-Kyu Kim. Nanoparticle-based therapeutic strategies for chronic liver diseases: Advances and insights. Liver Research, 2025, 9(2): 104-117 DOI:10.1016/j.livres.2025.04.002

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Authors’ contributions

Sathiyamoorthy Padmanaban: Writing e review & editing, Writing e original draft, Conceptualization. Ji-Won Baek: Writing e review & editing, Writing e original draft. Sai Sahithya Cha-marthy: Writing e original draft. Saipriya Chandrasekaran: Writing e original draft. Antony V Samrot: Supervision. Vijaya-kumar Gosu: Supervision. In-Kyu Park: Writing e review & edit-ing, Supervision, Funding acquisition. Kamalakannan Radhakrishnan: Writing e review & editing, Supervision. Don-Kyu Kim: Writing e review & editing, Supervision, Funding acquisition.

Declaration of competing interest

The authors declare that they have no conflict of interest.

Acknowledgements

This work was ﬁnancially supported by the National Research Foundation of Korea (NRF) grant funded by the Republic of Korea government (MSIT) (No. RS-2021-NR058546 and RS-2023-00219517 to Don-Kyu Kim; No. 2020R1A2C2005620, 2020R1A5A2031185, and 2020M3A9G3080282 to In-Kyu Park).

References

Publishing order | Descend order by publishing year | Descend order by cited within

[1]	Berasain C, Arechederra M, Argemí J, Fernández-Barrena MG, Avila MA. Loss of liver function in chronic liver disease: an identity crisis. J Hepatol. 2023;78: 401-414. https://doi.org/10.1016/j.jhep.2022.09.001.

[2]	Trefts E, Gannon M, Wasserman DH. The liver. Curr Biol. 2017;27: R1147eR1151. https://doi.org/10.1016/j.cub.2017.09.019.

[3]	Buechter M, Gerken G. Liver function-how to screen and to diagnose: insights from personal experiences, controlled clinical studies and future perspectives. J Pers Med. 2022;12:1657. https://doi.org/10.3390/jpm12101657.

[4]	Nagaratnam N, Nagaratnam K, Cheuk G. Chronic Liver Disease. Geriatric Dis-eases:Evaluation and Management. Switzerland: Springer International Pub-lishing AG; 2018:203e216. https://doi.org/10.1007/978-3-319-33434-9.

[5]	De Siervi S, Cannito S, Turato C. Chronic liver disease: latest research in pathogenesis, detection and treatment. Int J Mol Sci. 2023;24:10633. https://doi.org/10.3390/ijms241310633.

[6]	Huang DQ, Terrault NA, Tacke F, et al. Global epidemiology of cirrhosis d aetiology, trends and predictions. Nat Rev Gastroenterol Hepatol. 2023;20: 388-398. https://doi.org/10.1038/s41575-023-00759-2.

[7]	Fedeli U, Barbiellini Amidei C, Casotto V, et al. Mortality from chronic liver disease: recent trends and impact of the COVID-19 pandemic. World J Gas-troenterol. 2023;29:4166-4173. https://doi.org/10.3748/wjg.v29.i26.4166.

[8]	Asrani SK, Devarbhavi H, Eaton J, Kamath PS. Burden of liver diseases in the world. JHepatol. 2019;70:151-171. https://doi.org/10.1016/j.jhep.2018.09.014.

[9]	Ginès P, Krag A, Abraldes JG, Solà E, Fabrellas N, Kamath PS. Liver cirrhosis. Lancet. 2021;398:1359-1376. https://doi.org/10.1016/s0140-736(21)01374-x.

[10]	Wu XN, Xue F, Zhang N, et al. Global burden of liver cirrhosis and other chronic liver diseases caused by speciﬁc etiologies from 1990 to 2019. BMC Public Health. 2024;24:363. https://doi.org/10.1186/s12889-024-17948-6.

[11]	Gu L, Zhao C, Wang Y, et al. Senescence of hepatic stellate cells by speciﬁc delivery of manganese for limiting liver ﬁbrosis. Nano Lett. 2024;24: 1062-1073. https://doi.org/10.1021/acs.nanolett.3c03689.

[12]	Cardell K, Akerlind B, Sällberg M, Frydén A. Excellent response rate to a double dose of the combined hepatitis A and B vaccine in previous nonresponders to hepatitis B vaccine. J Infect Dis. 2008;198:299-304. https://doi.org/10.1086/589722.

[13]	Hoofnagle JH. Course and outcome of hepatitis C. Hepatology. 2002;36: S21eS29. https://doi.org/10.1053/jhep.2002.36227.

[14]	Wong VW, Ekstedt M, Wong GL-H, Hagström H. Changing epidemiology, global trends and implications for outcomes of NAFLD. J Hepatol. 2023;79: 842-852. https://doi.org/10.1016/j.jhep.2023.04.036.

[15]	Younossi ZM, Golabi P, Paik JM, Henry A, Van Dongen C, Henry L. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review. Hepatology. 2023;77: 1335-1347. https://doi.org/10.1097/HEP.0000000000000004.

[16]	Vetrano E, Rinaldi L, Mormone A, et al. Non-alcoholic fatty liver disease (NAFLD), type 2 diabetes, and non-viral hepatocarcinoma: pathophysiological mechanisms and new therapeutic strategies. Biomedicines. 2023;11:468. https://doi.org/10.3390/biomedicines11020468.

[17]	Jensen AH, Ytting H, Winther-Sørensen M, et al. Autoimmune liver diseases and diabetes. Eur J Gastroenterol Hepatol. 2023;35:938-947. https://doi.org/10.1097/MEG.0000000000002594.

[18]	Zeng J, Fan J, Zhou H. Bile acid-mediated signaling in cholestatic liver diseases. Cell Biosci. 2023;13:77. https://doi.org/10.1186/s13578-023-01035-1.

[19]	Lee MJ. A review of liver ﬁbrosis and cirrhosis regression. J Pathol Transl Med. 2023;57:189-195. https://doi.org/10.4132/jptm.2023.05.24.

[20]	Cai X, Chong Y, Gan W, Li X. Progress on clinical prognosis assessment in liver failure. Liver Res. 2023;7:101-107. https://doi.org/10.1016/j.livres.2023.05.004.

[21]	Sakasai-Sakai A, Takeda K, Takeuchi M. Involvement of intracellular TAGE and the TAGEeRAGEeROS axis in the onset and progression of NAFLD/NASH. Antioxidants (Basel). 2023;12:748. https://doi.org/10.3390/antiox12030748.

[22]	Banerjee P, Gaddam N, Chandler V, Chakraborty S. Oxidative stress-induced liver damage and remodeling of the liver vasculature. Am J Pathol. 2023;193:1400-1414. https://doi.org/10.1016/j.ajpath.2023.06.002.

[23]	Wang Y, Liu Y, Liu Y, et al. Remodeling liver microenvironment by L-arginine loaded hollow polydopamine nanoparticles for liver cirrhosis treatment. Biomaterials. 2023;295:122028. https://doi.org/10.1016/j.biomaterials.2023.122028.

[24]	Chung S, Lee CM, Zhang M. Advances in nanoparticle-based mRNA delivery for liver cancer and liver-associated infectious diseases. Nanoscale Horiz. 2022;8:10-28. https://doi.org/10.1039/d2nh00289b.

[25]	Unagolla JM, Das S, Flanagan R, Oehler M, Menon JU. Targeting chronic liver diseases: molecular markers, drug delivery strategies and future perspectives. Int J Pharm. 2024;660:124381. https://doi.org/10.1016/j.ijpharm.2024.124381.

[26]	Addissouky TA, Ali MMA, Sayed IETE, et al. Preclinical promise and clinical challenges for innovative therapies targeting liver ﬁbrogenesis. Arch Gastro-enterol Res. 2023;4:14-23. https://doi.org/10.33696/Gastroenterology.4.044.

[27]	Li F, Zhao Y, Cheng Z, et al. Restoration of sinusoid fenestrae followed by targeted nanoassembly delivery of an anti-ﬁbrotic agent improves treatment efﬁcacy in liver ﬁbrosis. Adv Mater. 2023;35:e2212206. https://doi.org/10.1002/adma.202212206.

[28]	Petagine L, Zariwala MG, Patel VB. Alcoholic liver disease: current insights into cellular mechanisms. World J Biol Chem. 2021;12:87e103. https://doi.org/10.4331/wjbc.v12.i5.87.

[29]	Teschke R. Alcoholic liver disease: alcohol metabolism, cascade of molecular mechanisms, cellular targets, and clinical aspects. Biomedicines. 2018;6:106. https://doi.org/10.3390/biomedicines6040106.

[30]	Cederbaum AI. Alcohol metabolism. Clin Liver Dis. 2012;16:667e685. https://doi.org/10.1016/j.cld.2012.08.002.

[31]	Seitz HK, Bataller R, Cortez-Pinto H, et al. Alcoholic liver disease. Nat Rev Dis Primers. 2018;4:16. https://doi.org/10.1038/s41572-018-0014-7.

[32]	Setshedi M, Wands JR, Monte SM. Acetaldehyde adducts in alcoholic liver disease. Oxid Med Cell Longev. 2010;3:178-185. https://doi.org/10.4161/oxim.3.3.12288.

[33]	Subramaniyan V, Lubau NSA, Mukerjee N, Kumarasamy V. Alcohol-induced liver injury in signalling pathways and curcumin’s therapeutic potential. Toxicol Rep. 2023;11:355-367. https://doi.org/10.1016/j.toxrep.2023.10.005.

[34]	Sharma P, Nandave M, Nandave D, et al. Reactive oxygen species (ROS)-mediated oxidative stress in chronic liver diseases and its mitigation by medicinal plants. Am J Transl Res. 2023;15:6321-6341.

[35]	Li BY, Peng WQ, Liu Y, Guo L, Tang QQ. HIGD1A links SIRT1 activity to adipose browning by inhibiting the ROS/DNA damage pathway. Cell Rep. 2023;42: 112731. https://doi.org/10.1016/j.celrep.2023.112731.

[36]	Hsu CL, Schnabl B. The guteliver axis and gut microbiota in health and liver disease. Nat Rev Microbiol. 2023;21:719-733. https://doi.org/10.1038/s41579-023-00904-3.

[37]	Raya Tonetti F, Eguileor A, Mrdjen M, et al. Gut-liver axis: recent concepts in pathophysiology in alcohol-associated liver disease. Hepatology. 2024;80: 1342-1371. https://doi.org/10.1097/HEP.0000000000000924.

[38]	Ait-Ahmed Y, Lafdil F. Novel insights into the impact of liver inflammatory responses on primary liver cancer development. Liver Res. 2023;7:26e34. https://doi.org/10.1016/j.livres.2023.01.001.

[39]	Zhao C, Xiao C, Feng S, Bai J. Artemisitene alters LPS-induced oxidative stress, inflammation and ferroptosis in liver through Nrf2/HO-1 and NF-kB pathway. Front Pharmacol. 2023;14:1177542. https://doi.org/10.3389/fphar.2023.1177542.

[40]	Trépo C, Chan HL, Lok A. Hepatitis B virus infection. Lancet. 2014;384: 2053-2063. https://doi.org/10.1016/S0140-6736(14)60220-8.

[41]	Westbrook RH, Dusheiko G. Natural history of hepatitis C. J Hepatol. 2014;61: S58eS68. https://doi.org/10.1016/j.jhep.2014.07.012.

[42]	El-Awady MK, Tabll AA, Redwan E-RM, et al. Flow cytometric detection of hepatitis C virus antigens in infected peripheral blood leukocytes: binding and entry. World J Gastroenterol. 2005;11:5203-5208. https://doi.org/10.3748/wjg.v11.i33.5203.

[43]	Yamada E, Montoya M, Schuettler CG, et al. Analysis of the binding of hepatitis C virus genotype 1a and 1b E 2 glycoproteins to peripheral blood mononuclear cell subsets. J Gen Virol. 2005;86:2507e2512. https://doi.org/10.1099/vir.0.81169-0.

[44]	Su J, Brunner L, Ates Oz E, et al. Activation of CD 4 T cells during prime im-munization determines the success of a therapeutic hepatitis B vaccine in HBV-carrier mouse models. J Hepatol. 2023;78:717e730. https://doi.org/10.1016/j.jhep.2022.12.013.

[45]	Liu Y, Caﬁero TR, Park D, et al. Targeted viral adaptation generates a simian-tropic hepatitis B virus that infects marmoset cells. Nat Commun. 2023;14: 3582. https://doi.org/10.1038/s41467-023-39148-3.

[46]	Burm R, Van Houtte F, Verhoye L, et al. A human monoclonal antibody against HBsAg for the prevention and treatment of chronic HBV and HDV infection. JHEP Rep. 2022;5:100646. https://doi.org/10.1016/j.jhepr.2022.100646.

[47]

Schmidt S, Mengistu M, Dafﬁs S, et al. Alternating arenavirus vector immu-nization generates robust polyfunctional genotype cross-reactive hepatitis B virusespeciﬁc CD 8 T-cell responses and high antiehepatitis B surface antigen titers. J Infect Dis. 2024;229:1077-1087. https://doi.org/10.1093/infdis/jiad340.

[48]	McKeating C, Cadden I, McDougall N, et al. Progression from acute to chronic hepatitis B is more common in older adults. Ulster Med J. 2018;87:177-180.

[49]	Irshad M, Mankotia DS, Irshad K. An insight into the diagnosis and patho-genesis of hepatitis C virus infection. World J Gastroenterol. 2013;19: 7896-7909. https://doi.org/10.3748/wjg.v19.i44.7896.

[50]	Csernalabics B, Marinescu MS, Maurer L, et al. Efﬁcient formation and main-tenance of humoral and CD 4 T-cell immunity targeting the viral capsid in acute-resolving hepatitis E infection. J Hepatol. 2024;80:564-575. https://doi.org/10.1016/j.jhep.2023.12.016.

[51]	Zhou YH, Zhao H. Immunobiology and host response to HEV. Adv Exp Med Biol. 2023;1417:93-118. https://doi.org/10.1007/978-981-99-1304-6_7.

[52]	He Q, Liu T, Yang X, et al. Optimization of immunosuppression strategies for the establishment of chronic hepatitis E virus infection in rabbits. J Virol. 2024;98:e0084624. https://doi.org/10.1128/jvi.00846-24.

[53]	Younossi Z, Anstee QM, Marietti M, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018;15:11-20. https://doi.org/10.1038/nrgastro.2017.109.

[54]	Tilg H, Moschen AR, Roden M. NAFLD and diabetes mellitus. Nat Rev Gastro-enterol Hepatol. 2017;14:32-42. https://doi.org/10.1038/nrgastro.2016.147.

[55]	Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology. 2018;67:123-133. https://doi.org/10.1002/hep.29466.

[56]	Alkhouri N, McCullough AJ. Noninvasive diagnosis of NASH and liver ﬁbrosis within the spectrum of NAFLD. Gastroenterol Hepatol (N Y). 2012;8:661-668.

[57]	Miura K, Yang L, van Rooijen N, Ohnishi H, Seki E. Hepatic recruitment of macrophages promotes nonalcoholic steatohepatitis through CCR2. Am J Physiol Gastrointest Liver Physiol. 2012;302:G1310eG1321. https://doi.org/10.1152/ajpgi.00365.2011.

[58]	Matsuda M, Seki E. Hepatic Stellate cell-macrophage crosstalk in liver ﬁbrosis and carcinogenesis. Semin Liver Dis. 2020;40:307-320. https://doi.org/10.1055/s-0040-1708876.

[59]	Seki E, Schnabl B. Role of innate immunity and the microbiota in liver ﬁbrosis: crosstalk between the liver and gut. J Physiol. 2012;590:447-458. https://doi.org/10.1113/jphysiol.2011.219691.

[60]	Ganz M, Szabo G. Immune and inflammatory pathways in NASH. Hepatol Int. 2013; 7(Suppl 2):771e781. https://doi.org/10.1007/s12072-013-9468-6.

[61]	Seki E, De Minicis S, Osterreicher CH, et al. TLR4 enhances TGF-beta signaling and hepatic ﬁbrosis. Nat Med. 2007;13:1324e1332. https://doi.org/10.1038/nm1663.

[62]	Devisscher L, Scott CL, Lefere S, et al. Non-alcoholic steatohepatitis induces transient changes within the liver macrophage pool. Cell Immunol. 2017;322: 74-83. https://doi.org/10.1016/j.cellimm.2017.10.006.

[63]	Lefere S, Degroote H, Van Vlierberghe H, Devisscher L. Unveiling the depletion of Kupffer cells in experimental hepatocarcinogenesis through liver macro-phage subtype-speciﬁc markers. J Hepatol. 2019;71:631e633. https://doi.org/10.1016/j.jhep.2019.03.016.

[64]	Calzadilla Bertot L, Adams LA. The natural course of non-alcoholic fatty liver disease. Int J Mol Sci. 2016;17:774. https://doi.org/10.3390/ijms17050774.

[65]	Song X, Sun J, Liu H, et al. Lycopene alleviates endoplasmic reticulum stress in steatohepatitis through inhibition of the ASK1eJNK signaling pathway. J Agric Food Chem. 2024;72:7832-7844. https://doi.org/10.1021/acs.jafc.3c08108.

[66]	Casillas-Ramírez A, Mosbah IB, Ramalho F, Roselló-Catafau J, Peralta C. Past and future approaches to ischemia-reperfusion lesion associated with liver transplantation. Life Sci. 2006;79:1881-1894. https://doi.org/10.1016/j.lfs.2006.06.024.

[67]	Saidi RF, Chang J, Brooks S, Nalbantoglu I, Adsay V, Jacobs MJ.Ischemic pre-conditioning and intermittent clamping increase the tolerance of fatty liver to hepatic ischemia-reperfusion injury in the rat. Transplant Proc. 2007;39:3010-3014. https://doi.org/10.1016/j.transproceed.2007.09.044.

[68]	Clavien PA, Harvey PR, Strasberg SM. Preservation and reperfusion injuries in liver allografts. An overview and synthesis of current studies. Transplantation. 1992;53:957-978. https://doi.org/10.1097/00007890-199205000-00001.

[69]	Gasbarrini A, Borle AB, Farghali H, Bender C, Francavilla A, Van Thiel D. Effect of anoxia on intracellular ATP, Naþ i, Ca2þ i, Mg2þ i, and cytotoxicity in rat hepatocytes. J Biol Chem. 1992;267:6654-6663.

[70]	Peralta C, Bartrons R, Riera L, et al. Hepatic preconditioning preserves energy metabolism during sustained ischemia. Am J Physiol Gastrointest Liver Physiol. 2000;279:G163eG171. https://doi.org/10.1152/ajpgi.2000.279.1.G163.

[71]	Mekala S, Tulimilli SV, Geesala R, Manupati K, Dhoke NR, Cellular crosstalk mediated by platelet-derived growth factor BB and transforming growth factor b during hepatic injury activates hepatic stellate cells. Can J Physiol Pharmacol. 2018;96:728-741. https://doi.org/10.1139/cjpp-2017-0768.

[72]	Seen S. Chronic liver disease and oxidative stressea narrative review. Expert Rev Gastroenterol Hepatol. 2021;15:1021-1035. https://doi.org/10.1080/17474124.2021.1949289.

[73]	Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact. 2006;160: 1-40. https://doi.org/10.1016/j.cbi.2005.12.009.

[74]	Collin F. Chemical basis of reactive oxygen species reactivity and involvement in neurodegenerative diseases. Int J Mol Sci. 2019;20:2407. https://doi.org/10.3390/ijms20102407.

[75]	Conde de la Rosa L, Goicoechea L, Torres S, Garcia-Ruiz C, Fernandez-Checa JC. Role of oxidative stress in liver disorders. Livers. 2022;2:283-314. https://doi.org/10.3390/livers2040023.

[76]	Veith A, Moorthy B. Role of cytochrome P450s in the generation and meta-bolism of reactive oxygen species. Curr Opin Toxicol. 2018;7:44-51. https://doi.org/10.1016/j.cotox.2017.10.003.

[77]	Noor MT, Manoria P. Immune dysfunction in cirrhosis. J Clin Transl Hepatol. 2017;5:50e58. https://doi.org/10.14218/JCTH.2016.00056.

[78]	Canbay A, Feldstein AE, Higuchi H, et al. Kupffer cell engulfment of apoptotic bodies stimulates death ligand and cytokine expression. Hepatology. 2003;38: 1188-1198. https://doi.org/10.1053/jhep.2003.50472.

[79]	Tsochatzis EA, Bosch J, Burroughs AK. Liver cirrhosis. Lancet. 2014;383: 1749-1761. https://doi.org/10.1016/s0140-6736(14)60121-5.

[80]	Torok NJ. Dysregulation of redox pathways in liver ﬁbrosis. Am J Physiol Gastrointest Liver Physiol. 2016;311:G667eG674. https://doi.org/10.1152/ajpgi.00050.2016.

[81]	Kroemer G, Mari-no G, Levine B. Autophagy and the integrated stress response. Mol Cell. 2010;40:280e293. https://doi.org/10.1016/j.molcel.2010.09.023.

[82]	Yonekawa T, Thorburn A. Autophagy and cell death. Essays Biochem. 2013;55: 105-117. https://doi.org/10.1042/bse0550105.

[83]	Ueno T, Komatsu M. Autophagy in the liver: functions in health and disease. Nat Rev Gastroenterol Hepatol. 2017;14:170-184. https://doi.org/10.1038/nrgastro.2016.185.

[84]	Boya P, González-Polo RA, Casares N, et al. Inhibition of macroautophagy triggers apoptosis. Mol Cell Biol. 2005;25:1025-1040. https://doi.org/10.1128/MCB.25.3.1025-1040.2005.

[85]	Nikoletopoulou V, Markaki M, Palikaras K, Tavernarakis N. Crosstalk between apoptosis, necrosis and autophagy. Biochim Biophys Acta. 2013;1833: 3448-3459. https://doi.org/10.1016/j.bbamcr.2013.06.001.

[86]	Wang K. Autophagy and apoptosis in liver injury. Cell Cycle. 2015;14: 1631-1642. https://doi.org/10.1080/15384101.2015.1038685.

[87]	Nagy LE, Ding WX, Cresci G, Saikia P, Shah VH. Linking pathogenic mecha-nisms of alcoholic liver disease with clinical phenotypes. Gastroenterology. 2016;150:1756-1768. https://doi.org/10.1053/j.gastro.2016.02.035.

[88]	Ding WX, Li M, Chen X, et al. Autophagy reduces acute ethanol-induced hepatotoxicity and steatosis in mice. Gastroenterology. 2010;139: 1740-1752. https://doi.org/10.1053/j.gastro.2010.07.041.

[89]	Eid N, Ito Y, Horibe A, Otsuki Y. Ethanol-induced mitophagy in liver is asso-ciated with activation of the PINK1-Parkin pathway triggered by oxidative DNA damage. Histol Histopathol. 2016;31:1143-1159. https://doi.org/10.14670/HH-11-747.

[90]	Williams JA, Ni HM, Ding Y, Ding WX. Parkin regulates mitophagy and mitochondrial function to protect against alcohol-induced liver injury and steatosis in mice. Am J Physiol Gastrointest Liver Physiol. 2015;309: G324eG340. https://doi.org/10.1152/ajpgi.00108.2015.

[91]	Lin CW, Zhang H, Li M, et al. Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and non-alcoholic fatty liver conditions in mice. JHepatol. 2013;58:993-999. https://doi.org/10.1016/j.jhep.2013.01.011.

[92]	Kharbanda KK, McVicker DL, Zetterman RK, MacDonald RG, Donohue Jr TM. Flow cytometric analysis of vesicular pH in rat hepatocytes after ethanol administration. Hepatology. 1997;26:929-934. https://doi.org/10.1002/hep.510260419.

[93]	Kharbanda KK, McVicker DL, Zetterman RK, Donohue Jr TM. Ethanol con-sumption alters trafﬁcking of lysosomal enzymes and affects the processing of procathepsin L in rat liver. Biochim Biophys Acta. 1996;1291:45-52. https://doi.org/10.1016/0304-4165(96)00043-8.

[94]	Thomes PG, Trambly CS, Fox HS, Tuma DJ, Donohue Jr TM.Acute and chronic ethanol administration differentially modulate hepatic autophagy and tran-scription factor EB. Alcohol Clin Exp Res. 2015; 39:2354-2363. https://doi.org/10.1111/acer.12904.

[95]	Chao X, Wang S, Zhao K, et al. Impaired TFEB-mediated lysosome biogenesis and autophagy promote chronic ethanol-induced liver injury and steatosis in mice. Gastroenterology. 2018;155:865e 879 (e12). https://doi.org/10.1053/j.gastro.2018.05.027.

[96]	Fukuo Y, Yamashina S, Sonoue H, et al. Abnormality of autophagic function and cathepsin expression in the liver from patients with non-alcoholic fatty liver disease. Hepatol Res. 2014;44:1026-1036. https://doi.org/10.1111/hepr.12282.

[97]	Yang L, Li P, Fu S, Calay ES, Hotamisligil GS. Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell Metab. 2010;11: 467-478. https://doi.org/10.1016/j.cmet.2010.04.005.

[98]	PapáčkováZ, DaňkováH, PálenićkováE, KazdováL, CahováM. Effectofshort-and long-term high-fat feeding on autophagy flux and lysosomal activity in rat liver. Physiol Res. 2012;61:S67eS76. https://doi.org/10.33549/physiolres.932394.

[99]	Miyagawa K, Oe S, Honma Y, Izumi H, Baba R, Harada M. Lipid-induced endoplasmic reticulum stress impairs selective autophagy at the step of autophagosome-lysosome fusion in hepatocytes. Am J Pathol. 2016;186: 1861-1873. https://doi.org/10.1016/j.ajpath.2016.03.003.

[100]

Tanaka S, Hikita H, Tatsumi T, et al. Rubicon inhibits autophagy and accel-erates hepatocyte apoptosis and lipid accumulation in nonalcoholic fatty liver disease in mice. Hepatology. 2016;64:1994-2014. https://doi.org/10.1002/hep.28820.

[101]

Settembre C, De Cegli R, Mansueto G, et al. TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop. Nat Cell Biol. 2013;15:647-658. https://doi.org/10.1038/ncb2718.

[102]

Park HW, Park H, Semple IA, et al. Pharmacological correction of obesity-induced autophagy arrest using calcium channel blockers. Nat Commun. 2014;5:4834. https://doi.org/10.1038/ncomms5834.

[103]

Sinha RA, Farah BL, Singh BK, et al. Caffeine stimulates hepatic lipid meta-bolism by the autophagy-lysosomal pathway in mice. Hepatology. 2014;59: 1366-1380. https://doi.org/10.1002/hep.26667.

[104]

Aishima S, Fujita N, Mano Y, et al. p62þ Hyaline inclusions in intrahepatic cholangiocarcinoma associated with viral hepatitis or alcoholic liver disease. Am J Clin Pathol. 2010;134:457-465. https://doi.org/10.1309/AJCP53YVVJCNDZIR.

[105]

Morishita H, Komatsu M. Role of autophagy in liver diseases. Curr Opin Physiol. 2022;30:100594. https://doi.org/10.1016/j.cophys.2022.100594.

[106]

González Grande R, Santaella Leiva I, López Ortega S, Jiménez Pérez M. Present and future management of viral hepatitis. World J Gastroenterol. 2021;27: 8081-8102. https://doi.org/10.3748/wjg.v27.i47.8081.

[107]

Fung J, Yuen MF, Yuen JC, Wong DK, Lai CL. Low serum HBV DNA levels and development of hepatocellular carcinoma in patients with chronic hepatitis B: a caseecontrol study. Aliment Pharmacol Ther. 2007;26:377-382. https://doi.org/10.1111/j.1365-2036.2007.03390.x.

[108]

Yuan HJ, Yuen MF, Ka-Ho Wong D, Sablon E, Lai CL. The relationship between HBV-DNA levels and cirrhosis-related complications in Chinese with chronic hepatitis B. J Viral Hepat. 2005;12:373-379. https://doi.org/10.1111/j.1365-2893.2005.00603.x.

[109]

Price AS, Nelson AK, Ghosh A, Kottilil S, Chua JV. A phase 2 open label study of ledipasvir/sofosbuvir for 12 weeks in subjects with hepatitis B virus infection. J Med Virol. 2023;95:e28105. https://doi.org/10.1002/jmv.28105.

[110]

Graf C, D’Ambrosio R, Degasperi E, et al. Real-world effectiveness of vox-ilaprevir/velpatasvir/sofosbuvir in patients following DAA failure. JHEP Rep. 2024;6:100994. https://doi.org/10.1016/j.jhepr.2023.100994.

[111]

Joines RW, Blatter M, Abraham B, et al. A prospective, randomized, compar-ative US trial of a combination hepatitis A and B vaccine (Twinrix) with corresponding monovalent vaccines (Havrix and Engerix-B) in adults. Vaccine. 2001;19:4710-4719. https://doi.org/10.1016/s0264-410x(01)00240-7.

[112]

Rodríguez JL, Valenzuela C, Marín N, et al. Comparative pharmacokinetics and pharmacodynamics of two recombinant human interferon alpha-2b formu-lations administered intramuscularly in healthy male volunteers. Biotecnol Apl. 2000;17:166-170.

[113]

Pecoraro V, Banzi R, Cariani E, et al. New direct-acting antivirals for the treatment of patients with hepatitis C virus infection: a systematic review of randomized controlled trials. J Clin Exp Hepatol. 2019;9:522e538. https://doi.org/10.1016/j.jceh.2018.07.004.

[114]

Scott LJ. Ledipasvir/sofosbuvir: a review in chronic hepatitis C. Drugs. 2018;78:245e256. https://doi.org/10.1007/s40265-018-0864-z.

[115]

Raven SF, Hoebe CJ, Vossen AC, et al. Serological response to three alternative series of hepatitis B revaccination (Fendrix, Twinrix, and HBVaxPro-40) in healthy non-responders: a multicentre, open-label, randomised, controlled, superiority trial. Lancet Infect Dis. 2020;20:92-101. https://doi.org/10.1016/S1473-3099(19)30417-7.

[116]

Yun JN, Yeun JS, Kan HS, et al. A randomized, open-label, crossover study to compare the safety and pharmacokinetics of two tablet formulations of tenofovir (tenofovir disoproxil and tenofovir disoproxil fumarate) in healthy subjects. Int J Clin Pharmacol Ther. 2020;58:749e756. https://doi.org/10.5414/CP203651.

[117]

Soriano V, Moreno-Torres V, Trevi-no A, Corral O, Bulevirtide in the treatment of hepatitis delta: drug discovery, clinical development and place in therapy. Drug Des Devel Ther. 2023;17:155-166. https://doi.org/10.2147/DDDT.S379964.

[118]

Yuen MF, Fung S, Ma X, et al. Long-term open-label vebicorvir for chronic HBV infection: safety and off-treatment responses. JHEP Rep. 2024;6:100999. https://doi.org/10.1016/j.jhepr.2023.100999.

[119]

Gane EJ, Schwabe C, Berliba E, et al. Safety, antiviral activity and pharmaco-kinetics of JNJ-64530440, a novel capsid assembly modulator, as 4 week monotherapy in treatment-naive patients with chronic hepatitis B virus infection. J Antimicrob Chemother. 2022;77:1102-1110. https://doi.org/10.1093/jac/dkab491.

[120]

Bazinet M, P^antea V, Cebotarescu V, et al. Safety and efﬁcacy of REP 2139 and pegylated interferon alfa-2a for treatment-naive patients with chronic hep-atitis B virus and hepatitis D virus co-infection (REP 301 and REP 301-LTF): a non-randomised, open-label, phase 2trial. Lancet Gastroenterol Hepatol. 2017; 2:877e889. https://doi.org/10.1016/S2468-1253(17)30288-1.

[121]

Gane EJ, Dunbar PR, Brooks AE, et al. Safety and efﬁcacy of the oral TLR8 agonist selgantolimod in individuals with chronic hepatitis B under viral suppression. J Hepatol. 2023;78:513-523. https://doi.org/10.1016/j.jhep.2022.09.027.

[122]

Gordon LB, Kleinman ME, Massaro J, et al. Clinical trial of the protein farne-sylation inhibitors lonafarnib, pravastatin, and zoledronic acid in children with Hutchinson-Gilford progeria syndrome. Circulation. 2016;134:114-125. https://doi.org/10.1161/CIRCULATIONAHA.116.022188.

[123]

Ezhilarasan D. Deciphering the molecular pathways of saroglitazar: a dual PPAR a/g agonist for managing metabolic NAFLD. Metabolism. 2024;155: 155912. https://doi.org/10.1016/j.metabol.2024.155912.

[124]

Liu L, Liu C, Zhao M, et al. The pharmacodynamic and differential gene expression analysis of PPAR a/d agonist GFT 505 in CDAHFD-induced NASH model. PLoS One. 2020;15:e0243911. https://doi.org/10.1371/journal.pone.0243911.

[125]

Francque SM, Bedossa P, Ratziu V, et al. A randomized, controlled trial of the Pan-PPAR agonist laniﬁbranor in NASH. N Engl J Med. 2021;385:1547-1558. https://doi.org/10.1056/NEJMoa2036205.

[126]

Lai LL, Vethakkan SR, Nik Mustapha NR, Mahadeva S, Chan WK. Empagliflozin for the treatment of nonalcoholic steatohepatitis in patients with type 2 diabetes mellitus. Dig Dis Sci. 2020;65:623-631. https://doi.org/10.1007/s10620-019-5477-1.

[127]

Lu W, Zhou Z, Jiang N, Han J.An updated patent review of GLP-1 receptor agonists ( 2020-present). Expert Opin Ther Pat. 2023; 33:597-612. https://doi.org/10.1080/13543776.2023.2274905.

[128]

Dissanayake HA, Somasundaram NP. Polyagonists in type 2 diabetes man-agement. Curr Diab Rep. 2024;24:1-12. https://doi.org/10.1007/s11892-023-01530-2.

[129]

Loomba R, Mohseni R, Lucas KJ, et al. TVB-2640 (FASN inhibitor) for the treatment of nonalcoholic steatohepatitis: FASCINATE-1, a randomized, placebo-controlled phase 2a trial. Gastroenterology. 2021;161:1475-1486. https://doi.org/10.1053/j.gastro.2021.07.025.

[130]

Etzion O, Bareket-Samish A, Yardeni D, Fishman P. Namodenoson at the crossroad of metabolic dysfunction-associated steatohepatitis and hepato-cellular carcinoma. Biomedicines. 2024;12:848. https://doi.org/10.3390/biomedicines12040848.

[131]

Choudhary NS, Duseja A. Genetic and epigenetic disease modiﬁers: non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). Transl Gastroenterol Hepatol. 2021;6:2. https://doi.org/10.21037/tgh.2019.09.06.

[132]

Hassanein T, McClain CJ, Vatsalya V, et al. Safety, pharmacokinetics, and ef-ﬁcacy signals of larsucosterol (DUR-928) in alcohol-associated hepatitis. Am J Gastroenterol. 2024;119:107e115. https://doi.org/10.14309/ajg.0000000000 002275.

[133]

Cheng Z, Yang L, Chu H. The role of gut microbiota, exosomes, and their interaction in the pathogenesis of ALD. J Adv Res. 2025; 72:353-367. https://doi.org/10.1016/j.jare.2024.07.002.

[134]

Zhang T, Zhao Q, Ye F, Huang CY, Chen WM, Huang WQ. Alda-1, an ALDH2 activator, protects against hepatic ischemia/reperfusion injury in rats via in-hibition of oxidative stress. Free Radic Res. 2018;52:629-638. https://doi.org/10.1080/10715762.2018.1459042.

[135]

Tang L, Zhao C, Zhang J, et al. Discussion on the mechanism of Gandoufumu Decoction attenuates liver damage of Wilson’s disease by inhibiting auto-phagy through the PI3K/Akt/mTOR pathway based on network pharmacology and experimental veriﬁcation. Mediators Inflamm. 2023;2023:3236911. https://doi.org/10.1155/2023/3236911.

[136]

Kudo M. A new era in systemic therapy for hepatocellular carcinoma: ate-zolizumab plus bevacizumab combination therapy. Liver Cancer. 2020;9: 119-137. https://doi.org/10.1159/000505189.

[137]

Kudo M. Durvalumab plus tremelimumab in unresectable hepatocellular carcinoma. Hepatobiliary Surg Nutr. 2022;11:592-596. https://doi.org/10.21037/hbsn-22-143.

[138]

Brethauer SA, Chand B, Schauer PR. Risks and beneﬁts of bariatric surgery: current evidence. Cleve Clin J Med. 2006;73:993-1007. https://doi.org/10.3949/ccjm.73.11.993.

[139]

Lomonaco R, Sunny NE, Bril F, Cusi K. Nonalcoholic fatty liver disease: current issues and novel treatment approaches. Drugs. 2013;73:1-14. https://doi.org/10.1007/s40265-012-0004-0.

[140]

Singal AK, Mathurin P. Diagnosis and treatment of alcohol-associated liver disease: a review. JAMA. 2021;326:165-176. https://doi.org/10.1001/jama.2021.7683.

[141]

Crabb DW, Im GY, Szabo G, Mellinger JL, Lucey MR. Diagnosis and treatment of alcohol-associated liver diseases: 2019 practice guidance from the Amer-ican Association for the Study of Liver Diseases. Hepatology. 2020;71: 306-333. https://doi.org/10.1002/hep.30866.

[142]

Yang JD, Nakamura I, Roberts LR. The tumor microenvironment in hepato-cellular carcinoma: current status and therapeutic targets. Semin Cancer Biol. 2011;21:35-43. https://doi.org/10.1016/j.semcancer.2010.10.007.

[143]

Bruix J, Boix L, Sala M, Llovet JM. Focus on hepatocellular carcinoma. Cancer Cell. 2004;5:215-219. https://doi.org/10.1016/s1535-6108(04)00058-3.

[144]

Berasain C, Castillo J, Perugorria MJ, Latasa MU, Prieto J, Avila MA. Inflam-mation and liver cancer: new molecular links. Ann N Y Acad Sci. 2009;1155: 206-221. https://doi.org/10.1111/j.1749-6632.2009.03704.x.

[145]

Capece D, Fischietti M, Verzella D, et al. The inflammatory microenvironment in hepatocellular carcinoma: a pivotal role for tumor-associated macro-phages. BioMed Res Int. 2013;2013:187204. https://doi.org/10.1155/2013/187204.

[146]

Solinas G, Germano G, Mantovani A, Allavena P. Tumor-associated macro-phages (TAM) as major players of the cancer-related inflammation. J Leukoc Biol. 2009;86:1065e1073. https://doi.org/10.1189/jlb.0609385.

[147]

Porta C, Larghi P, Rimoldi M, et al. Cellular and molecular pathways linking inflammation and cancer. Immunobiology. 2009;214:761-777. https://doi.org/10.1016/j.imbio.2009.06.014.

[148]

Abenavoli L, Izzo AA, Milić N, Cicala C, Santini A, Capasso R. Milk thistle (Silybum marianum): a concise overview on its chemistry, pharmacological, and nutraceutical uses in liver diseases. Phytother Res. 2018;32:2202-2213. https://doi.org/10.1002/ptr.6171.

[149]

Adelusi OB, Ramachandran A, Lemasters JJ, Jaeschke H. The role of Iron in lipid peroxidation and protein nitration during acetaminophen-induced liver injury in mice. Toxicol Appl Pharmacol. 2022;445:116043. https://doi.org/10.1016/j.taap.2022.116043.

[150]

Shariﬁ-Rigi A, Heidarian E, Amini SA. Protective and anti-inflammatory effects of hydroalcoholic leaf extract of Origanum vulgare on oxidative stress, TNF-a gene expression and liver histological changes in paraquat-induced hepato-toxicity in rats. Arch Physiol Biochem. 2019;125:56-63. https://doi.org/10.1080/13813455.2018.1437186.

[151]

Papackova Z, Heczkova M, Dankova H, et al. Silymarin prevents acetaminophen-induced hepatotoxicity in mice. PLoS One. 2018;13:e0191353. https://doi.org/10.1371/journal.pone.0191353.

[152]

Zhang J, Song Q, Han X, et al. Multi-targeted protection of acetaminophen-induced hepatotoxicity in mice by tannic acid. Int Immunopharmacol. 2017;47:95e105. https://doi.org/10.1016/j.intimp.2017.03.027.

[153]

Maradana MR, Yekollu SK, Zeng B, et al. Immunomodulatory liposomes tar-geting liver macrophages arrest progression of nonalcoholic steatohepatitis. Metabolism. 2018;78:80-94. https://doi.org/10.1016/j.metabol.2017.09.002.

[154]

Yan B, Zheng X, Wang Y, et al. Liposome-based silibinin for mitigating nonalcoholic fatty liver disease: dual effects via parenteral and intestinal routes. ACS Pharmacol Transl Sci. 2023;6:1909-1923. https://doi.org/10.1021/acsptsci.3c00210.

[155]

Chen C, Jie X, Ou Y, et al. Nanoliposome improves inhibitory effects of nar-ingenin on nonalcoholic fatty liver disease in mice. Nanomedicine (Lond). 2017;12:1791-1800. https://doi.org/10.2217/nnm-2017-0119.

[156]

Liu J, Yuan Y, Gong X, et al. Baicalin and its nanoliposomes ameliorates nonalcoholic fatty liver disease via suppression of TLR4 signaling cascade in mice. Int Immunopharmacol. 2020;80:106208. https://doi.org/10.1016/j.intimp.2020.106208.

[157]

Park HJ, Cho JY, Kim MK, et al. Anti-obesity effect of Schisandra chinensis in 3T3-L 1 cells and high fat diet-induced obese rats. Food Chem. 2012;134: 227-234. https://doi.org/10.1016/j.foodchem.2012.02.101.

[158]

Jang MK, Nam JS, Kim JH, et al. Schisandra chinensis extract ameliorates nonalcoholic fatty liver via inhibition of endoplasmic reticulum stress. J Ethnopharmacol. 2016;185:96e104. https://doi.org/10.1016/j.jep.2016. 03.021.

[159]

Wang K, Chen H, Zheng J, Chen J, Chen Y, Yuan Y. Engineered liposomes targeting hepatic stellate cells overcome pathological barriers and reverse liver ﬁbrosis. J Control Release. 2024;368:219-232. https://doi.org/10.1016/j.jconrel.2024.02.022.

[160]

Li Y, Zhang T, Liu Q, et al. Mixed micelles loaded with the 5-benzylidenethiazolidine-2,4-dione derivative SKLB 023 for efﬁcient treat-ment of non-alcoholic steatohepatitis. Int J Nanomedicine. 2019;14: 3943-3953. https://doi.org/10.2147/IJN.S202821.

[161]

Pan Y, Zhang Y, Ouyang H, et al. Targeted delivery of celastrol via chondroitin sulfate derived hybrid micelles for alleviating symptoms in nonalcoholic fatty liver disease. ACS Appl Bio Mater. 2023;6:4877-4893. https://doi.org/10.1021/acsabm.3c00612.

[162]

Shashni B, Tajika Y, Ikeda Y, Nishikawa Y, Nagasaki Y. Self-assembling polymer-based short chain fatty acid prodrugs ameliorate non-alcoholic steatohepatitis and liver ﬁbrosis. Biomaterials. 2023;295:122047. https://doi.org/10.1016/j.biomaterials.2023.122047.

[163]

Zhao R, Zhu M, Zhou S, Feng W, Chen H. Rapamycin-loaded mPEG-PLGA nanoparticles ameliorate hepatic steatosis and liver injury in non-alcoholic fatty liver disease. Front Chem. 2020;8:407. https://doi.org/10.3389/fchem.2020.00407.

[164]

Ebaid H, Al-Tamimi J, Hassan I, et al. Effect of selenium nanoparticles on carbon tetrachloride-induced hepatotoxicity in the Swiss albino rats. Appl Sci. 2021;11:3044. https://doi.org/10.3390/app11073044.

[165]

Oró D, Yudina T, Fernández-Varo G, et al. Cerium oxide nanoparticles reduce steatosis, portal hypertension and display anti-inflammatory properties in rats with liver ﬁbrosis. J Hepatol. 2016;64:691e698. https://doi.org/10.1016/j.jhep.2015.10.020.

[166]

Liu M, Wu H, Li Q, et al. Mn3O 4 nanozymes prevent acetaminophen-induced acute liver injury by attenuating oxidative stress and countering inflamma-tion. J Colloid Interface Sci. 2024;654:83-95. https://doi.org/10.1016/j.jcis.2023.10.019.

[167]

Shulman M, Cohen M, Soto-Gutierrez A, et al. Enhancement of naringenin bioavailability by complexation with hydroxypropyl-b-cyclodextrin. PLoS One. 2011;6:e18033. https://doi.org/10.1371/journal.pone.0018033.

[168]

Zobeiri M, Belwal T, Parvizi F, et al. Naringenin and its nano-formulations for fatty liver: cellular modes of action and clinical perspective. Curr Pharm Bio-technol. 2018;19:196e205. https://doi.org/10.2174/1389201019666180514170122.

[169]

Zhu M, Fan H, Deng J, et al. BMI 1 silencing liposomes suppress post-radiotherapy cancer stemness against radioresistant hepatocellular carci-noma. ACS Nano. 2023;17:23405-23421. https://doi.org/10.1021/acsnano.3c04636.

[170]

Ding Y, Zhang S, Sun Z, et al. Preclinical validation of silibinin/albumin nanoparticles as an applicable system against acute liver injury. Acta Biomater. 2022;146:385e395. https://doi.org/10.1016/j.actbio.2022.04.021.

[171]

Calvo-Castro LA, Schiborr C, David F, et al. The oral bioavailability of trans-resveratrol from a grapevine-shoot extract in healthy humans is signiﬁ-cantly increased by micellar solubilization. Mol Nutr Food Res. 2018;62: e1701057. https://doi.org/10.1002/mnfr.201701057.

[172]

Atanacković M, Posa M, Heinle H, Gojković-Bukarica L, Cvejić J. Solubilization of resveratrol in micellar solutions of different bile acids. Colloids Surf B Bio-interfaces. 2009;72:148e154. https://doi.org/10.1016/j.colsurfb.2009.03.029.

[173]

Chimento A, De Amicis F, Sirianni R, et al. Progress to improve oral bioavailability and beneﬁcial effects of resveratrol. Int J Mol Sci. 2019;20:1381. https://doi.org/10.3390/ijms20061381.

[174]

Sergides C, Chirilă M, Silvestro L, Pitta D, Pittas A. Bioavailability and safety study of resveratrol 500 mg tablets in healthy male and female volunteers. Exp Ther Med. 2016;11:164-170. https://doi.org/10.3892/etm.2015.2895.

[175]

Kapetanovic IM, Muzzio M, Huang Z, Thompson TN, McCormick DL. Phar-macokinetics, oral bioavailability, and metabolic proﬁle of resveratrol and its dimethylether analog, pterostilbene, in rats. Cancer Chemother Pharmacol. 2011;68:593-601. https://doi.org/10.1007/s00280-010-1525-4.

[176]

Schneider P, Zhang H, Simic L, et al. Multicompartment polyion complex micelles based on triblock polypept(o)ides mediate efﬁcient siRNA delivery to cancer-associated ﬁbroblasts for antistromal therapy of hepatocellular carci-noma. Adv Mater. 2024;36:e2404784. https://doi.org/10.1002/adma.2024 04784.

[177]

Padmanaban S, Pully D, Samrot AV, et al. Rising influence of nanotechnology in addressing oxidative stress-related liver disorders. Antioxidants (Basel). 2023;12:1405. https://doi.org/10.3390/antiox12071405.

[178]

Kumar S, Adjei IM, Brown SB, Liseth O, Sharma B. Manganese dioxide nano-particles protect cartilage from inflammation-induced oxidative stress. Bio-materials. 2019;224:119467. https://doi.org/10.1016/j.biomaterials. 2019.119467.

[179]

Nelson BC, Johnson ME, Walker ML, Riley KR, Sims CM. Antioxidant cerium oxide nanoparticles in biology and medicine. Antioxidants (Basel). 2016;5:15. https://doi.org/10.3390/antiox5020015.

[180]

Bashandy SAE, Alaamer A, Moussa SAA, Omara EA. Role of zinc oxide nano-particles in alleviating hepatic ﬁbrosis and nephrotoxicity induced by thio-acetamide in rats. Can J Physiol Pharmacol. 2018;96:337-344. https://doi.org/10.1139/cjpp-2017-0247.

[181]

Carvajal S, Perramón M, Oró D, et al. Cerium oxide nanoparticles display antilipogenic effect in rats with non-alcoholic fatty liver disease. Sci Rep. 2019;9:12848. https://doi.org/10.1038/s41598-019-49262-2.

[182]

Carvajal S, Perramón M, Casals G, et al. Cerium oxide nanoparticles protect against oxidant injury and interfere with oxidative mediated kinase signaling in human-derived hepatocytes. Int J Mol Sci. 2019;20:5959. https://doi.org/10.3390/ijms20235959.

[183]

Parra-Robert M, Casals E, Massana N, et al. Beyond the scavenging of reactive oxygen species (ROS): direct effect of cerium oxide nanoparticles in reducing fatty acids content in an in vitro model of hepatocellular steatosis. Bio-molecules. 2019;9:425. https://doi.org/10.3390/biom9090425.

[184]

Hald Albertsen C, Kulkarni JA, Witzigmann D, Lind M, Petersson K, Simonsen JB. The role of lipid components in lipid nanoparticles for vaccines and gene therapy. Adv Drug Deliv Rev. 2022;188:114416. https://doi.org/10.1016/j.addr.2022.114416.

[185]

Nosova AS, Koloskova OO, Nikonova AA, et al. Diversity of PEGylation methods of liposomes and their influence on RNA delivery. Medchemcomm. 2019;10:369e377. https://doi.org/10.1039/c8md00515j.

[186]

Samuelsson E, Shen H, Blanco E, Ferrari M, Wolfram J. Contribution of Kupffer cells to liposome accumulation in the liver. Colloids Surf B Biointerfaces. 2017;158:356e362. https://doi.org/10.1016/j.colsurfb.2017.07.014.

[187]

Shah VM, Nguyen DX, Patel P, et al. Liposomes produced by microfluidics and extrusion: a comparison for scale-up purposes. Nanomedicine. 2019;18: 146-156. https://doi.org/10.1016/j.nano.2019.02.019.

[188]

Xiao L, Hou Y, Xue Z, et al. Soy protein isolate/genipin-based nanoparticles for the stabilization of pickering emulsion to design self-healing guar gum-based hydrogels. Biomacromolecules. 2023;24:2087-2099. https://doi.org/10.1021/acs.biomac.2c01507.

[189]

Mehta V, Karnam G, Madgula V. Liver-on-chips for drug discovery and development. Mater Today Bio. 2024;27:101143. https://doi.org/10.1016/j.mtbio.2024.101143.

[190]

Zhang Q, Yin R, Guan G, Liu H, Song G. Renal clearable magnetic nanoparticles for magnetic resonance imaging and guided therapy. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2024;16:e1929. https://doi.org/10.1002/wnan.1929.

[191]

Geszke-Moritz M, Moritz M. Biodegradable polymeric nanoparticle-based drug delivery systems: comprehensive overview, perspectives and chal-lenges. Polymers (basel). 2024;16:2536. https://doi.org/10.3390/polym16172536.

[192]

Wang YL, Lee YH, Chou CL, Chang YS, Liu WC, Chiu HW. Oxidative stress and potential effects of metal nanoparticles: a review of biocompatibility and toxicity concerns. Environ Pollut. 2024;346:123617. https://doi.org/10.1016/j.envpol.2024.123617.

[193]

Catenacci L, Rossi R, Sechi F, et al. Effect of lipid nanoparticle physico-chemical properties and composition on their interaction with the immune system. Pharmaceutics. 2024;16:1521. https://doi.org/10.3390/pharmaceutics16121521.