Autophagy-mediated Kupffer cell polarization in liver cirrhosis reversal: Mechanistic insights and therapeutic strategies

Abstract

Liver cirrhosis, an advanced end-stage liver disease characterized by extensive hepatic fibrosis, is a leading cause of mortality and morbidity worldwide. Despite its prevalence, there is no specific treatment to prevent fibrosis progression, with liver transplantation remaining the only definitive option for patients with advanced cirrhotic liver disease. The activation of hepatic stellate cells (HSCs) by proinflammatory M1-type Kupffer cells (KCs) is a key driver of fibrosis. Activated HSCs further exacerbate fibrosis by recruiting bone marrow-derived macrophages (BMDMs) through chemokine signaling, which induces alpha-smooth muscle actin (alpha-SMA) expression. Autophagy, a cellular process responsible for degrading damaged organelles and protein aggregates, is vital for maintaining liver physiology and metabolic balance. It also plays a significant role in the pathogenesis of fibrosis. Compounds that promote KC autophagy can polarize KCs toward an anti-inflammatory M2 phenotype, disrupting signaling pathways that activate HSCs and recruit BMDMs to injured liver tissue. This approach has been identified as a promising therapeutic strategy to combat liver fibrosis. This review highlights various strategies to activate KC autophagy and modulate KC polarization, offering insights into novel therapeutic targets for treating liver fibrosis and preventing cirrhosis progression.

Keywords

Liver cirrhosis / Hepatic fibrosis / Kupffer cells (KCs) / Hepatic stellate cells (HSCs) / Macrophage / Macrophage polarization

Authors' contributions

Debjeet Sur: Writing - review & editing, Writing - original draft, Conceptualization. Gargi Banik: Writing - review & editing, Visualization.

Declaration of competing interest

The authors declare that there is no conflicts of interest.

Acknowledgements

The authors did not receive any financial support for authorship and/or publication of this article.

References

[1] Higashi T, Friedman SL, Hoshida Y. Hepatic stellate cells as key target in liver fibrosis. Adv Drug Deliv Rev. 2017; 121:27-42. https://doi.org/10.1016/J.ADDR.2017.05.007.

[2] Berumen J, Baglieri J, Kisseleva T, Mekeel K. Liver fibrosis: pathophysiology and clinical implications. WIREs Mechanisms of Disease. 2021; 13:e1499. https://doi.org/10.1002/wsbm.1499.

[3] Acharya N, Sabatos-Peyton C, Anderson AC. Tim-3 finds its place in the cancer immunotherapy landscape. J Immunother Cancer. 2020; 8:e000911. https://doi.org/10.1136/jitc-2020-000911.

[4] Wen JH, Li DY, Liang S, Yang C, Tang JX, Liu HF. Macrophage autophagy in macrophage polarization, chronic inflammation and organ fibrosis. Front Immunol. 2022; 13:946832. https://doi.org/10.3389/fimmu.2022.946832.

[5] Puche JE, Saiman Y, Friedman SL. Hepatic stellate cells and liver fibrosis. Compr Physiol. 2013; 3:1473-1492. https://doi.org/10.1002/cphy.c120035.

[6] Brennan PN, MacMillan M, Manship T, et al. Study protocol: a multicentre, open-label, parallel-group, phase 2, randomised controlled trial of autolo-gous macrophage therapy for liver cirrhosis (MATCH). BMJ Open. 2021; 11: e053190. https://doi.org/10.1136/bmjopen-2021-053190.

[7] Zhou JC, Wang JL, Ren HZ, Shi XL.Autophagy plays a double-edged sword role in liver diseases. J Physiol Biochem. 2022; 78:9-17. https://doi.org/10.1007/s13105-021-00844-7.

[8] Yin XM, Ding WX, Gao W. Autophagy in the liver. Hepatology. 2008; 47: 1773-1785. https://doi.org/10.1002/HEP.22146.

[9] Thoen LF, Guimaraes EL, Grunsven LA. Autophagy: a new player in hepatic stellate cell activation. Autophagy. 2012; 8:126-128. https://doi.org/10.4161/auto.8.1.18105.

[10] Pinzani M. Pathophysiology of liver fibrosis. Dig Dis. 2015; 33:492-497. https://doi.org/10.1159/000374096.

[11] Shiani A, Narayanan S, Pena L, Friedman M. The role of diagnosis and treatment of underlying liver disease for the prognosis of primary liver cancer. Cancer Control. 2017; 24:1073274817729240. https://doi.org/10.1177/1073274817729240.

[12] Jaroszewicz J, Flisiak-Jackiewicz M, Lebensztejn D, Flisiak R. Current drugs in early development for treating hepatitis C virus-related hepatic fibrosis. Expert Opin Investig Drugs. 2015; 24:1229-1239. https://doi.org/10.1517/13543784.2015.1057568.

[13] Kouroumalis E, Voumvouraki A, Augoustaki A, Samonakis DN. Autophagy in liver diseases. World J Hepatol. 2021; 13:6-65. https://doi.org/10.4254/wjh.v13.i1.6.

[14] Rautou PE, Mansouri A, Lebrec D, Durand F, Valla D, Moreau R. Autophagy in liver diseases. J Hepatol. 2010; 53:1123-1134. https://doi.org/10.1016/j.jhep.2010.07.006.

[15] Yu L, Chen Y, Tooze SA. Autophagy pathway: cellular and molecular mech-anisms. Autophagy. 2018; 14:207-215. https://doi.org/10.1080/15548627.2017.1378838.

[16] Ke PY. Diverse functions of autophagy in liver physiology and liver diseases. Int J Mol Sci. 2019; 20:300. https://doi.org/10.3390/ijms20020300.

[17] Zhang Q, Li Y, Miao C, et al. Anti-angiogenesis effect of Neferine via regu-lating autophagy and polarization of tumor-associated macrophages in high- grade serous ovarian carcinoma. Cancer Lett. 2018; 432:144-155. https://doi.org/10.1016/j.canlet.2018.05.049.

[18] Chen P, Cescon M, Bonaldo P. Autophagy-mediated regulation of macro-phages and its applications for cancer. Autophagy. 2014; 10:192-200. https://doi.org/10.4161/auto.26927.

[19] Liu K, Zhao E, Ilyas G, et al. Impaired macrophage autophagy increases the immune response in obese mice by promoting proinflammatory macrophage polarization. Autophagy. 2015; 11:271-284. https://doi.org/10.1080/15548627.2015.1009787.

[20] Padmanaban S, Baek JW, Chamarthy SS, et al. Nanoparticle-based therapeutic strategies for chronic liver diseases: Advances and insights. Liver Res. 2025; 9: 104-117. https://doi.org/10.1016/j.livres.2025.04.002.

[21] Hu Z, Chen G, Yan C, et al. Autophagy affects hepatic fibrosis progression by regulating macrophage polarization and exosome secretion. Environ Toxicol. 2023; 38:1665-1677. https://doi.org/10.1002/tox.23795.

[22] Moreira RK. Hepatic stellate cells and liver fibrosis. Arch Pathol Lab Med. 2007; 131:1728-1734. https://doi.org/10.5858/2007-131-1728-HSCALF.

[23] Ezhilarasan D, Sokal E, Najimi M. Hepatic fibrosis: it is time to go with he-patic stellate cell-specific therapeutic targets. Hepatobiliary Pancreat Dis Int. 2018; 17:192-197. https://doi.org/10.1016/j.hbpd.2018.04.003.

[24] Böttcher K, Pinzani M. Pathophysiology of liver fibrosis and the methodo-logical barriers to the development of anti-fibrogenic agents. Adv Drug Deliv Rev. 2017; 121:3-8. https://doi.org/10.1016/j.addr.2017.05.016.

[25] Mak KM, Wu C, Cheng CP. Lipid droplets, the Holy Grail of hepatic stellate cells: in health and hepatic fibrosis. Anat Rec (Hoboken). 2023; 306:983-1010. https://doi.org/10.1002/ar.25138.

[26] Lucantoni F, Martínez-Cerezuela A, Gruevska A, et al. Understanding the implication of autophagy in the activation of hepatic stellate cells in liver fibrosis: are we there yet? J Pathol. 2021; 254:216-228. https://doi.org/10.1002/path.5678.

[27] Czaja MJ, Ding WX, Donohue TM, et al. Functions of autophagy in normal and diseased liver. Autophagy. 2013; 9:1131-1158. https://doi.org/10.4161/auto.25063.

[28] Wang C, Ma C, Gong L, et al. Macrophage polarization and its role in liver disease. Front Immunol. 2021; 12:803037. https://doi.org/10.3389/fimmu.2021.803037.

[29] Han J, Zhang X, Lau JKC, et al. Bone marrow-derived macrophage contributes to fibrosing steatohepatitis through activating hepatic stellate cells. J Pathol. 2019; 248:488-500. https://doi.org/10.1002/path.5275.

[30] Lemoinne S, Thabut D, Housset C. Portal myofibroblasts connect angiogenesis and fibrosis in liver. Cell Tissue Res. 2016; 365:583-589. https://doi.org/10.1007/s00441-016-2443-5.

[31] Gao J, Wei B, de Assuncao TM, et al. Hepatic stellate cell autophagy inhibits extracellular vesicle release to attenuate liver fibrosis. J Hepatol. 2020; 73: 1144-1154. https://doi.org/10.1016/j.jhep.2020.04.044.

[32] Arthur MJP, Fibrogenesis II. Metalloproteinases and their inhibitors in liver fibrosis. Am J Physiol Gastrointest Liver Physiol. 2000;279:G245-G249. https://doi.org/10.1152/ajpgi.2000.279.2.G245.

[33] Cursio R, Colosetti P, Codogno P, Cuervo AM, Shen HM. The role of autophagy in liver diseases: mechanisms and potential therapeutic targets. Biomed Res Int. 2015; 2015:480508. https://doi.org/10.1155/2015/480508.

[34] Ignat SR, Dinescu S, Hermenean A, Costache M. Cellular interplay as a consequence of inflammatory signals leading to liver fibrosis development. Cells. 2020; 9:461. https://doi.org/10.3390/cells9020461.

[35] Song Y, Zhao Y, Wang F, Tao L, Xiao J, Yang C. Autophagy in hepatic fibrosis. Biomed Res Int. 2014; 2014:436242. https://doi.org/10.1155/2014/436242.

[36] Mastoridou EM, Goussia AC, Glantzounis GK, Kanavaros P, Charchanti AV. Autophagy and exosomes: cross-regulated pathways playing major roles in hepatic stellate cells activation and liver fibrosis. Front Physiol. 2022; 12: 801340. https://doi.org/10.3389/fphys.2021.801340.

[37] Liu C, Tao Q, Sun M, et al. Kupffer cells are associated with apoptosis, inflammation and fibrotic effects in hepatic fibrosis in rats. Lab Invest. 2010; 90:1805-1816. https://doi.org/10.1038/labinvest.2010.123.

[38] Hernández-Gea V, Ghiassi-Nejad Z, Rozenfeld R, et al. Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues. Gastroenterology. 2012; 142:938-946. https://doi.org/10.1053/j.gastro.2011.12.044.

[39] Leveque L, Le Texier L, Lineburg KE, Hill GR, MacDonald KP. Autophagy and haematopoietic stem cell transplantation. Immunol Cell Biol. 2015; 93:43-50. https://doi.org/10.1038/icb.2014.95.

[40] Schon HT, Bartneck M, Borkham-Kamphorst E, et al. Pharmacological inter-vention in hepatic stellate cell activation and hepatic fibrosis. Front Phar-macol. 2016; 7:33. https://doi.org/10.3389/fphar.2016.00033.

[41] Zheng W, Zhou J, Song S, et al. Dipeptidyl-peptidase 4 inhibitor sitagliptin ameliorates hepatic insulin resistance by modulating inflammation and autophagy in ob/ob mice. Int J Endocrinol. 2018; 2018:8309723. https://doi.org/10.1155/2018/8309723.

[42] Vyas K, Patel MM. Insights on drug and gene delivery systems in liver fibrosis. Asian J Pharm Sci. 2023; 18:100779. https://doi.org/10.1016/j.ajps.2023.100779.

[43] Ilyas G, Cingolani F, Zhao E, Tanaka K, Czaja MJ. Decreased macrophage autophagy promotes liver injury and inflammation from alcohol. Alcohol Clin Exp Res. 2019; 43:1403-1413. https://doi.org/10.1111/acer.14041.

[44] Zhao X, Tang X, Guo N, et al. Biochanin a enhances the defense against sal-monella enterica infection through AMPK/ULK1/mTOR-Mediated autophagy and extracellular traps and reversing SPI-1-dependent macrophage (MΦ) M2 polarization. Front Cell Infect Microbiol. 2018; 8:318. https://doi.org/10.3389/fcimb.2018.00318.

[45] Shiau DJ, Kuo WT, Davuluri GVN, et al. Hepatocellular carcinoma-derived high mobility group box 1 triggers M2 macrophage polarization via a TLR2/NOX2/autophagy axis. Sci Rep. 2020; 10:13582. https://doi.org/10.1038/s41598-020-70137-4.

[46] Qian H, Chao X, Williams J, et al. Autophagy in liver diseases: a review. Mol Aspects Med. 2021; 82:100973. https://doi.org/10.1016/j.mam.2021.100973.

[47] Mastoridou EM, Goussia AC, Glantzounis GK, Kanavaros P, Charchanti AV. Autophagy and exosomes: cross-regulated pathways playing major roles in hepatic stellate cells activation and liver fibrosis. Front Physiol. 2021; 12: 801340. https://doi.org/10.3389/fphys.2021.801340.

[48] Fukada H, Yamashina S, Izumi K, et al. Suppression of autophagy sensitizes Kupffer cells to endotoxin. Hepatol Res. 2012; 42:1112-1118. https://doi.org/10.1111/j.1872-034X.2012.01024.x.

[49] Ramachandran P, Pellicoro A, Vernon MA, et al. Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis. Proc Natl Acad Sci U S A. 2012; 109: E3186-E3195. https://doi.org/10.1073/pnas.1119964109.

[50] Ju C, Tacke F. Hepatic macrophages in homeostasis and liver diseases: from pathogenesis to novel therapeutic strategies. Cell Mol Immunol. 2016; 13: 316-327. https://doi.org/10.1038/cmi.2015.104.

[51] Graubardt N, Vugman M, Mouhadeb O, et al. Ly6Chi monocytes and their macrophage descendants regulate neutrophil function and clearance in acetaminophen-induced liver injury. Front Immunol. 2017; 8:626. https://doi.org/10.3389/fimmu.2017.00626.

[52] Das LM, Binko AM, Traylor ZP, Peng H, Lu KQ. Vitamin D improves sunburns by increasing autophagy in M2 macrophages. Autophagy. 2019; 15:813-826. https://doi.org/10.1080/15548627.2019.1569298.

[53] Louvet A, Teixeira-Clerc F, Chobert MN, et al. Cannabinoid CB2 receptors protect against alcoholic liver disease by regulating Kupffer cell polarization in mice. Hepatology. 2011; 54:1217-1226. https://doi.org/10.1002/hep.24524.

[54] Elchaninov AV, Fatkhudinov TK, Vishnyakova PA, Lokhonina AV, Sukhikh GT. Phenotypical and functional polymorphism of liver resident macrophages. Cells. 2019; 8:1032. https://doi.org/10.3390/cells8091032.

[55] Chang CP, Su YC, Lee PH, Lei HY. Targeting NFKB by autophagy to polarize hepatoma-associated macrophage differentiation. Autophagy. 2013; 9: 619-621. https://doi.org/10.4161/auto.23546.

[56] MacPhee PJ, Schmidt EE, Groom AC. Evidence for Kupffer cell migration along liver sinusoids, from high-resolution in vivo microscopy. Am J Physiol. 1992;263:G17-G23. https://doi.org/10.1152/ajpgi.1992.263.1.G17.

[57] Billiar TR, Curran RD. Hepatocyte and Kupffer Cell Interactions (1992). In Bouwens L, Wisse E, eds. Boca Raton: CRC Press; 2017:3-22.

[58] Liu Z, Ren J, Qiu C, Wang Y, Zhang T. Application of mesenchymal stem cells in liver fibrosis and regeneration. Liver Res. 2024; 8:246-258. https://doi.org/10.1016/j.livres.2024.11.004.

[59] Komori T, Morikawa Y. Essential roles of the cytokine oncostatin M in crosstalk between muscle fibers and immune cells in skeletal muscle after aerobic exercise. J Biol Chem. 2022; 298:102686. https://doi.org/10.1016/j.jbc.2022.102686.

[60] Zhu S, Zhang J, Zhang L, et al. Inhibition of Kupffer cell autophagy abrogates nanoparticle-induced liver injury. Adv Healthc Mater. 2017;6. https://doi.org/10.1002/adhm.201601252,2017;6:10.1002/adhm.201601252.

[61] Wardle EN. Kupffer cells and their function. Liver. 1987; 7:63-75. https://doi.org/10.1111/j.1600-0676.1987.tb00319.x.

[62] Kolios G, Valatas V, Kouroumalis E. Role of Kupffer cells in the pathogenesis of liver disease. World J Gastroenterol. 2006; 12:7413-7420. https://doi.org/10.3748/wjg.v12.i46.7413.

[63] Su GL. Lipopolysaccharides in liver injury: molecular mechanisms of Kupffer cell activation. Am J Physiol Gastrointest Liver Physiol. 2002;283:G256-G265. https://doi.org/10.1152/ajpgi.00550.2001.

[64] Nakashima H, Ogawa Y, Shono S, et al. Activation of CD11b+ Kupffer cells/ macrophages as a common cause for exacerbation of TNF/Fas-Ligand-dependent hepatitis in hypercholesterolemic mice. PLoS One. 2013; 8: e49339. https://doi.org/10.1371/journal.pone.0049339.

[65] Endo-Umeda K, Nakashima H, Komine-Aizawa S, Umeda N, Seki S, Makishima M. Liver X receptors regulate hepatic F4/80 + CD11b+ Kupffer cells/macrophages and innate immune responses in mice. Sci Rep. 2018; 8: 9281. https://doi.org/10.1038/s41598-018-27615-7.

[66] Naito M, Hasegawa G, Ebe Y, Yamamoto T. Differentiation and function of Kupffer cells. Med Electron Microsc. 2004; 37:16-28. https://doi.org/10.1007/s00795-003-0228-x.

[67] Parola M, Pinzani M. Liver fibrosis: pathophysiology, pathogenetic targets and clinical issues. Mol Aspects Med. 2019; 65:37-55. https://doi.org/10.1016/j.mam.2018.09.002.

[68] Liu T, Wang L, Liang P, et al. USP19 suppresses inflammation and promotes M2-like macrophage polarization by manipulating NLRP3 function via autophagy. Cell Mol Immunol. 2021; 18:2431-2442. https://doi.org/10.1038/s41423-020-00567-7.

[69] Tabakhiyan F, Mir A, Vahedian V. Potential tumor marker for hepatocellular carcinoma identification: PI3K and pro-inflammatory cytokines (TGF-β IL-1, and IL-6). Horm Mol Biol Clin Investig. 2022; 43:389-396. https://doi.org/10.1515/hmbci-2022-0028.

[70] Nieto N. Oxidative-stress and IL-6 mediate the fibrogenic effects of rodent Kupffer cells on stellate cells. Hepatology. 2006; 44:1487-1501. https://doi.org/10.1002/hep.21427.

[71] Borkham-Kamphorst E, Alexi P, Tihaa L, Haas U, Weiskirchen R. Platelet- derived growth factor-D modulates extracellular matrix homeostasis and remodeling through TIMP-1 induction and attenuation of MMP-2 and MMP- 9 gelatinase activities. Biochem Biophys Res Commun. 2015; 457:307-313. https://doi.org/10.1016/j.bbrc.2014.12.106.

[72] Mantovani A, Sica A, Locati M. Macrophage polarization comes of age. Im-munity. 2005; 23:344-346. https://doi.org/10.1016/j.immuni.2005.10.001.

[73] Sica A, Erreni M, Allavena P, Porta C. Macrophage polarization in pathology. Cell Mol Life Sci. 2015; 72:4111-4126. https://doi.org/10.1007/s00018-015-1995-y.

[74] Chaterjee O, Sur D. Artificially induced in situ macrophage polarization: an emerging cellular therapy for immuno-inflammatory diseases. Eur J Phar-macol. 2023; 957:176006. https://doi.org/10.1016/j.ejphar.2023.176006.

[75] Cheng D, Chai J, Wang H, Fu L, Peng S, Ni X. Hepatic macrophages: key players in the development and progression of liver fibrosis. Liver Int. 2021; 41:2279-2294. https://doi.org/10.1111/liv.14940.

[76] Nguyen-Lefebvre AT, Horuzsko A. Kupffer cell metabolism and function. J Enzymol Metab. 2015; 1:101.

[77] Park JK, Shao M, Kim MY, et al. An endoplasmic reticulum protein, Nogo-B, facilitates alcoholic liver disease through regulation of kupffer cell polari-zation. Hepatology. 2017; 65:1720-1734. https://doi.org/10.1002/hep.29051.

[78] Pellicoro A, Ramachandran P, Iredale JP, Fallowfield JA. Liver fibrosis and repair: immune regulation of wound healing in a solid organ. Nat Rev Immunol. 2014; 14:181-194. https://doi.org/10.1038/nri3623.

[79] Zhang S, Xie F, Li K, et al. Gold nanoparticle-directed autophagy intervention for antitumor immunotherapy via inhibiting tumor-associated macrophage M2 polarization. Acta Pharm Sin B. 2022; 12:3124-3138. https://doi.org/10.1016/j.apsb.2022.02.008.

[80] Tsuji Y, Kuramochi M, Golbar HM, Izawa T, Kuwamura M, Yamate J. Acet-aminophen-induced rat hepatotoxicity based on M1/M2-macrophage po-larization, in possible relation to damage-associated molecular patterns and autophagy. Int J Mol Sci. 2020; 21:8998. https://doi.org/10.3390/ijms21238998.

[81] Li W, Zhu S, Li J, et al. EGCG stimulates autophagy and reduces cytoplasmic HMGB1 levels in endotoxin-stimulated macrophages. Biochem Pharmacol. 2011; 81:1152-1163. https://doi.org/10.1016/j.bcp.2011.02.015.

[82] Chen S, Saeed AFUH, Liu Q, et al. Macrophages in immunoregulation and therapeutics. Signal Transduct Target Ther. 2023; 8:207. https://doi.org/10.1038/s41392-023-01452-1.

[83] Ge J, Li H, Yang JQ, et al. Autophagy in hepatic macrophages can be regulator and potential therapeutic target of liver diseases: a review. Medicine (Balti-more). 2023; 102:e33698. https://doi.org/10.1097/MD.0000000000033698.

[84] Hung TM, Hsiao CC, Lin CW, Lee PH. Complex cell type-specific roles of autophagy in liver fibrosis and cirrhosis. Pathogens. 2020; 9:225. https://doi.org/10.3390/pathogens9030225.

[85] Zubova SG, Suvorova II, Karpenko MN. Macrophage and microglia polariza-tion: focus on autophagy-dependent reprogramming. Front Biosci (Schol Ed). 2022; 14:3. https://doi.org/10.31083/j.fbs1401003.

[86] Lodder J, Denaes T, Chobert MN, et al. Macrophage autophagy protects against liver fibrosis in mice. Autophagy. 2015; 11:1280-1292. https://doi.org/10.1080/15548627.2015.1058473.

[87] Beljaars L, Schippers M, Reker-Smit C, et al. Hepatic localization of macro-phage phenotypes during fibrogenesis and resolution of fibrosis in mice and humans. Front Immunol. 2014; 5:430. https://doi.org/10.3389/fimmu.2014.00430.

[88] Feng L, Song P, Xu F, et al. cis-Khellactone Inhibited the proinflammatory macrophages via promoting autophagy to ameliorate imiquimod-induced psoriasis. J Invest Dermatol. 2019; 139:1946- 1956(e3). https://doi.org/10.1016/j.jid.2019.02.021.

[89] Dai E, Han L, Liu J, et al. Autophagy-dependent ferroptosis drives tumor- associated macrophage polarization via release and uptake of oncogenic KRAS protein. Autophagy. 2020; 16:2069-2083. https://doi.org/10.1080/15548627.2020.1714209.

[90] Qiu P, Liu Y, Zhang J. Review: the role and mechanisms of macrophage autophagy in sepsis. Inflammation. 2019; 42:6-19. https://doi.org/10.1007/s10753-018-0890-8.

[91] Deust A, Chobert MN, Demontant V, et al. Macrophage autophagy protects against hepatocellular carcinogenesis in mice. Sci Rep. 2021; 11:1-16. https://doi.org/10.1038/s41598-021-98203-5.

[92] Nakahira K, Haspel JA, Rathinam VA, et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol. 2011; 12:222-230. https://doi.org/10.1038/ni.1980.

[93] Sun WY, Choi J, Cha YJ, Koo JS. Evaluation of the expression of amine oxidase proteins in breast cancer. Int J Mol Sci. 2017; 18:2775. https://doi.org/10.3390/ijms18122775.

[94] Cotzomi-Ortega I, Nieto-Ya-nez O, Juárez-Avelar I, et al. Autophagy inhibition in breast cancer cells induces ROS-mediated MIF expression and M1 macrophage polarization. Cell Signal. 2021; 86:110075. https://doi.org/10.1016/j.cellsig.2021.110075.

[95] Wu Y, Joseph B, Gupta S. Immunosuppression using the mTOR inhibition mechanism affects replacement of rat liver with transplanted cells. Hep-atology. 2006; 44:410-419. https://doi.org/10.1002/hep.21277.

[96] Wang J, Deng M, Wu H, et al. Suberoylanilide hydroxamic acid alleviates orthotopic liver transplantation-induced hepatic ischemia-reperfusion injury by regulating the AKT/GSK3β/NF-κB and AKT/mTOR pathways in rat Kupffer cells. Int J Mol Med. 2020; 45:1875-1887. https://doi.org/10.3892/ijmm.2020.4551.

[97] Cao H, Jia Q, Yan L, Chen C, Xing S, Shen D. Quercetin suppresses the pro-gression of atherosclerosis by regulating MST1-mediated autophagy in ox- LDL-induced RAW264.7 macrophage foam cells. Int J Mol Sci. 2019; 20: 6093. https://doi.org/10.3390/ijms20236093.

[98] Zaffagnini G, Martens S. Mechanisms of selective autophagy. J Mol Biol. 2016; 428:1714-1724. https://doi.org/10.1016/j.jmb.2016.02.004.

[99] Tan HY, Wang N, Man K, Tsao SW, Che CM, Feng Y. 52 activation mediates tumour-associated macrophage repolarisation and suppression of hepatocellular carcinoma by natural compound baicalin. Cell Death Dis. 2015; 6:e1942. https://doi.org/10.1038/cddis.2015.271.

[100] Sanjurjo L, Aran G, Téllez É, et al. CD5L promotes M2 macrophage polari-zation through autophagy-mediated upregulation of ID3. Front Immunol. 2018; 9:480. https://doi.org/10.3389/fimmu.2018.00480.

[101] Xu XS, Feng ZH, Cao D, et al. SCARF1 promotes M2 polarization of Kupffer cells via calcium-dependent PI3K-AKT-STAT3 signalling to improve liver trans-plantation. Cell Prolif. 2021; 54:e13022. https://doi.org/10.1111/cpr.13022.

[102] Jiménez-Garcia L, Herránz S, Luque A, Hortelano S. Critical role of p 38 MAPK in IL-4-induced alternative activation of peritoneal macrophages. Eur J Immunol. 2015; 45:273-286. https://doi.org/10.1002/eji.201444806.

[103] Liu P, Huang G, Wei T, et al. Sirtuin 3-induced macrophage autophagy in regulating NLRP3 inflammasome activation. Biochim Biophys Acta Mol Basis Dis. 2018; 1864:764-777. https://doi.org/10.1016/j.bbadis.2017.12.027.

[104] Gracia-Sancho J, Guixé-Muntet S, Hide D, Bosch J. Modulation of autophagy for the treatment of liver diseases. Expet Opin Investig Drugs. 2014; 23: 965-977. https://doi.org/10.1517/13543784.2014.912274.

[105] Kucsera D.Targeting IL-1β and Assessing Sex Specific Molecular Differences in Mouse Models of Non-alcoholic Steatohepatitis. 2023.

[106] Tu Y, Fang QJ, Sun W, et al. Total flavones of abelmoschus manihot remodels gut microbiota and inhibits microinflammation in chronic renal failure progres-sion by targeting autophagy-mediated macrophage polarization. Front Phar-macol. 2020; 11:566611. https://doi.org/10.3389/fphar.2020.566611.

[107] Pinheiro RO, Nunes MP, Pinheiro CS, et al. Induction of autophagy correlates with increased parasite load of Leishmania amazonensis in BALB/c but not C57BL/6 macrophages. Microbes Infect. 2009; 11:181-190. https://doi.org/10.1016/j.micinf.2008.11.006.

[108] Jin MM, Wang F, Qi D, et al. A critical role of autophagy in regulating microglia polarization in neurodegeneration. Front Aging Neurosci. 2018; 10: 378. https://doi.org/10.3389/fnagi.2018.00378.

[109] Feng L, Song P, Xu F, et al. cis-khellactone inhibited the proinflammatory macrophages via promoting autophagy to ameliorate imiquimod-induced psoriasis. J Invest Dermatol. 2019;139:1946- 1956 (e3). https://doi.org/10.1016/j.jid.2019.02.021.

[110] Lau DT, Negash A, Chen J, et al. Innate immune tolerance and the role of kupffer cells in differential responses to interferon therapy among patients with HCV genotype 1 infection. Gastroenterology. 2013;144:402- 413 (e12). https://doi.org/10.1053/j.gastro.2012.10.044.

[111] Wang X, Wang J, Peng H, Zuo L, Wang H. Role of immune cell interactions in alcohol-associated liver diseases. Liver Res. 2024; 8:72-82. https://doi.org/10.1016/j.livres.2024.06.002.

[112] Covarrubias AJ, Aksoylar HI, Horng T. Control of macrophage metabolism and activation by mTOR and Akt signaling. Semin Immunol. 2015; 27:286-296. https://doi.org/10.1016/j.smim.2015.08.001.

[113] Wu MY, Lu JH. Autophagy and macrophage functions: inflammatory response and phagocytosis. Cells. 2019; 9:70. https://doi.org/10.3390/cells9010070.

[114] Wu BM, Liu JD, Li YH, Li J. Margatoxin mitigates CCl4-induced hepatic fibrosis in mice via macrophage polarization, cytokine secretion and STAT signaling. Int J Mol Med. 2020; 45:103-114. https://doi.org/10.3892/ijmm.2019.4395.

[115] Basak P, Maitra P, Khan U, et al. Capsaicin inhibits Shigella flexneri intracel-lular growth by inducing autophagy. Front Pharmacol. 2022; 13:903438. https://doi.org/10.3389/fphar.2022.903438.

[116] Xu J, Lv H. PSTPIP2 alleviates obesity associated adipose tissue inflammation and insulin resistance in diabetes mice through promoting M2 macrophage polarization via activation of PPARγ. J Diabet Complications. 2023; 37:108479. https://doi.org/10.1016/j.jdiacomp.2023.108479.

[117] Williams-Bey Y, Boularan C, Vural A, et al. Omega-3 free fatty acids suppress macrophage inflammasome activation by inhibiting NF-κB activation and enhancing autophagy. PLoS One. 2014; 9:e97957. https://doi.org/10.1371/journal.pone.0097957.

[118] Liu H, Zhou K, Liao L, Zhang T, Yang M, Sun C. Lipoxin A 4 receptor agonist BML-111 induces autophagy in alveolar macrophages and protects from acute lung injury by activating MAPK signaling. Respir Res. 2018; 19:243. https://doi.org/10.1186/s12931-018-0937-2.

[119] Cui SN, Chen ZY, Yang XB, et al. Trichostatin A modulates the macrophage phenotype by enhancing autophagy to reduce inflammation during poly-microbial sepsis. Int Immunopharmacol. 2019; 77:105973. https://doi.org/10.1016/j.intimp.2019.105973.

[120] Du L, Li Y, Liu W. Maresin 1 regulates autophagy and inflammation in human periodontal ligament cells through glycogen synthase kinase-3β/β-catenin pathway under inflammatory conditions. Arch Oral Biol. 2018; 87:242-247. https://doi.org/10.1016/j.archoralbio.2017.12.023.

[121] Li X, Guo G, Shen F, Kong L, Liang F, Sun G. Moxibustion activates macro-phage autophagy and protects experimental mice against bacterial infection. Evid Based Complement Alternat Med. 2014; 2014:450623. https://doi.org/10.1155/2014/450623.

[122] Pant R, Kabeer SW, Sharma S, et al. Pharmacological inhibition of DNMT1 restores macrophage autophagy and M2 polarization in Western diet- induced nonalcoholic fatty liver disease. J Biol Chem. 2023; 299:104779. https://doi.org/10.1016/j.jbc.2023.104779.

[123] Profumo E, Maggi E, Arese M, et al. Neuropeptide Y promotes human M2 macrophage polarization and enhances p62/SQSTM1-dependent autophagy and NRF 2 activation. Int J Mol Sci. 2022; 23:13009. https://doi.org/10.3390/ijms232113009.

[124] Zhou S, Gu J, Liu R, et al. Spermine alleviates acute liver injury by inhibiting liver-resident macrophage pro-inflammatory response through ATG5- dependent autophagy. Front Immunol. 2018; 9:948. https://doi.org/10.3389/fimmu.2018.00948.

[125] Luo J, He Y, Meng F, Yan N, Zhang Y, Song W. The role of autophagy in M2 polarization of macrophages induced by micro/nano topography. Int J Nanomed. 2020; 15:7763-7774. https://doi.org/10.2147/IJN.S270100.

[126] Fang X, Lan X, Zhu M, et al. Puerarin induces macrophage M2 polarization to exert antinonalcoholic steatohepatitis pharmacological activity via the acti-vation of autophagy. J Agric Food Chem. 2024; 72:7187-7202. https://doi.org/10.1021/acs.jafc.3c09601.

[127] Chen W, Li X, Guo S, et al. Tanshinone IIA harmonizes the crosstalk of autophagy and polarization in macrophages via miR-375/KLF4 pathway to attenuate atherosclerosis. Int Immunopharmacol. 2019; 70:486-497. https://doi.org/10.1016/j.intimp.2019.02.054.

[128] Liu Y, Zhou Q, Ye F, Yang C, Jiang H. Gut microbiota-derived short-chain fatty acids promote prostate cancer progression via inducing cancer cell auto-phagy and M2 macrophage polarization. Neoplasia. 2023; 43:100928. https://doi.org/10.1016/j.neo.2023.100928.

[129] Zhang X, Qin Y, Wan X, et al. Rosuvastatin exerts anti-atherosclerotic effects by improving macrophage-related foam cell formation and polarization conversion via mediating autophagic activities. J Transl Med. 2021; 19:1-16. https://doi.org/10.1186/s12967-021-02727-3.

[130] He T, Li W, Song Y, et al. Sestrin2 regulates microglia polarization through mTOR-mediated autophagic flux to attenuate inflammation during experi-mental brain ischemia. J Neuroinflammation. 2020; 17:329. https://doi.org/10.1186/s12974-020-01987-y.

[131] Qing L, Fu J, Wu P, Zhou Z, Yu F, Tang J. Metformin induces the M2 macro-phage polarization to accelerate the wound healing via regulating AMPK/ mTOR/NLRP3 inflammasome singling pathway. Am J Transl Res. 2019; 11: 655-668.

[132] Liu B, Deng X, Jiang Q, et al. Scoparone improves hepatic inflammation and autophagy in mice with nonalcoholic steatohepatitis by regulating the ROS/ P38/Nrf2 axis and PI3K/AKT/mTOR pathway in macrophages. Biomed Pharmacother. 2020; 125:109895. https://doi.org/10.1016/j.biopha.2020.109895.

[133] Shrivastava R, Asif M, Singh V, et al. M2 polarization of macrophages by Oncostatin M in hypoxic tumor microenvironment is mediated by mTORC2 and promotes tumor growth and metastasis. Cytokine. 2019; 118:130-143. https://doi.org/10.1016/j.cyto.2018.03.032.

[134] Kang C, Sang Q, Liu D, Wang L, Li J, Liu X. Polyphyllin I alleviates neuro-inflammation after cerebral ischemia-reperfusion injury via facilitating autophagy-mediated M2 microglial polarization. Mol Med. 2024; 30:59. https://doi.org/10.1186/s10020-024-00828-5.

[135] Wang L, Wu JP, He XJ. Butylphthalide has an anti-inflammatory role in spinal cord injury by promoting macrophage/microglia M2 polarization via p38 phosphorylation. Spine (Phila Pa 1976). 2020;45:E1066-E1076. https://doi.org/10.1097/BRS.0000000000003503.

[136] Guo FF, Meng FG, Zhang XN, Zeng T. Spermidine inhibits LPS-induced pro- inflammatory activation of macrophages by acting on Nrf2 signaling but not autophagy. J Funct Foods. 2022; 94:105115. https://doi.org/10.1016/j.jff.2022.105115.

[137] Ma Y, Pei T, Song L, et al. Flavonoids from Smilax China L. Rhizome improve chronic pelvic inflammatory disease by promoting macrophage reprogram-ming via the NLRP3 inflammasome-autophagy pathway. J Funct Foods. 2023; 109:105802. https://doi.org/10.1016/j.jff.2023.105802.

[138] Zhang Y, Cheng J, Su Y, Li M, Wen J, Li S. Cordycepin induces M1/M2 macrophage polarization to attenuate the liver and lung damage and im-munodeficiency in immature mice with sepsis via NF-κB/p65 inhibition. J Pharm Pharmacol. 2022; 74:227-235. https://doi.org/10.1093/jpp/rgab162.

[139] Zhao Q, Chen L, Zhang X, Yang H, Li Y, Li P. β-elemene promotes microglial M2-like polarization against ischemic stroke via AKT/mTOR signaling axis- mediated autophagy. Chin Med. 2024; 19:86. https://doi.org/10.1186/s13020-024-00946-6.

[140] Saha S, Profumo E, Togna AR, Riganò R, Saso L, Buttari B. Lupeol counteracts the proinflammatory signalling triggered in macrophages by 7-Keto-cholesterol: new perspectives in the therapy of atherosclerosis. Oxid Med Cell Longev. 2020; 2020:1232816. https://doi.org/10.1155/2020/1232816.

[141] Nie Y, Liang J, Sun J, Li J, Zhai X, Zhao P. Orexin A alleviates LPS-induced acute lung injury by inhibiting macrophage activation through JNK-mediated autophagy. Int Immunopharmacol. 2023; 124:111018. https://doi.org/10.1016/j.intimp.2023.111018.

[142] Lu S, Luo Y, Zhou P, Yang K, Sun G, Sun X. Ginsenoside compound K protects human umbilical vein endothelial cells against oxidized low-density lipo-protein-induced injury via inhibition of nuclear factor-κB, p38, and JNK MAPK pathways. J Ginseng Res. 2019; 43:95-104. https://doi.org/10.1016/j.jgr.2017.09.004.

[143] Yasueda A, Kayama H, Murohashi M, et al. Sanguisorba officinalis L. derived from herbal medicine prevents intestinal inflammation by inducing auto-phagy in macrophages. Sci Rep. 2020; 10:9972. https://doi.org/10.1038/s41598-020-65306-4.