Nicotinic acid protects against hepatic ischemia-reperfusion injury via suppressing mitochondrial damage-induced ferroptosis

Qian Zeng; Yina Sun; Mengzhen Lei; Zihan Liu; Xijing Yan; Rong Li; Jun Zheng; Jiandong Zha; Lijun Zhang; Xiaoling Guan; Jia Yao

doi:10.1016/j.livres.2025.11.001

Liver Research ›› 2025, Vol. 9 ›› Issue (4) :324 -337. DOI: 10.1016/j.livres.2025.11.001

Original Articles

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Nicotinic acid protects against hepatic ischemia-reperfusion injury via suppressing mitochondrial damage-induced ferroptosis

Qian Zeng ^a^,^b^,¹
, Yina Sun ^c^,¹
, Mengzhen Lei ^d^,¹
, Zihan Liu ^f^,¹
, Xijing Yan ^g
, Rong Li ^a^,^b^,^h
, Jun Zheng ^a^,^b^,^h
, Jiandong Zha ⁱ^,^*
, Lijun Zhang ^e^,^**
, Xiaoling Guan ^c^,^***
, Jia Yao ^a^,^b^,^****

Author information +

^a Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China

^b Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine, Guangzhou, Guangdong, China

^c Department of Laboratory Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China

^d Operation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China

^e Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China

^f First Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China

^g Department of Breast and Thyroid Surgery, Lingnan Hospital, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China

^h Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China

ⁱ Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong, China

^* Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong, China. E-mail addresses: zhajd@hku-szh.org (Jiandong Zha)

^** Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. E-mail addresses: zhanglj57@mail.sysu.edu.cn (Lijun Zhang)

^*** Department of Laboratory Medicine, The Third Affili-ated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. E-mail addresses: guanxling3@mail.sysu.edu.cn (Xiaoling Guan)

^**** Department of Hepatic Surgery and Liver Trans-plantation Center of the Third Affiliated Hospital of Sun Yat-sen University, Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine, Guangzhou, Guangdong, China. E-mail addresses: yaojia6@mail.sysu.edu.cn (Jia Yao).

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Abstract

Background and aims: Hepatic ischemia-reperfusion injury (HIRI) is a major contributor to liver dysfunction and failure, particularly in the context of liver transplantation. Its pathogenesis is primarily driven by ferroptosis, oxidative stress, and mitochondrial dysfunction. Given the interplay among these mechanisms through redox imbalance and disrupted energy metabolism, nicotinic acid (NA)-recognized for its antioxidative and metabolic regulatory properties-emerges as a promising therapeutic candidate. This study aims to investigate the protective effects of NA on HIRI and elucidate its underlying mechanisms.

Methods: An HIRI model in mice and a hypoxia/reoxygenation (H/R) model in primary hepatocytes were established to evaluate the effects of NA treatment on oxidative stress. NA was administered prior to model induction. N-acetylcysteine (NAC) was used as a comparator. Comprehensive assessments of ferroptosis, oxidative stress, mitophagy, and mitochondrial biogenesis markers were conducted using Western blotting, immunohistochemistry, immunofluorescence, and biochemical assays.

Results: NA pretreatment reduced serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase (LDH) levels, suppressed inflammation by decreasing neutrophil infiltration and macrophage activation, and mitigated oxidative stress by lowering reactive oxygen species (ROS) and malondialdehyde (MDA) levels. It enhanced antioxidant defenses, inhibited ferroptosis, and improved mitochondrial health through increased mitophagy, mitochondrial biogenesis, and mitochondrial permeability transition pore (mPTP) stabilization, leading to enhanced ATP production and mitochondrial function in HIRI.

Conclusions: NA improves mitochondrial function by promoting mitophagy and mitochondrial biogenesis, which reduces ferroptosis and oxidative stress, thereby alleviating HIRI.

Keywords

Nicotinic acid (NA) / Ferroptosis / Hepatic ischemia-reperfusion injury (HIRI) / Mitophagy / Mitochondrial biogenesis

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Qian Zeng, Yina Sun, Mengzhen Lei, Zihan Liu, Xijing Yan, Rong Li, Jun Zheng, Jiandong Zha, Lijun Zhang, Xiaoling Guan, Jia Yao. Nicotinic acid protects against hepatic ischemia-reperfusion injury via suppressing mitochondrial damage-induced ferroptosis. Liver Research, 2025, 9(4): 324-337 DOI:10.1016/j.livres.2025.11.001

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Authors’ contributions

Qian Zeng, Yina Sun, Mengzhen Lei, and Zihan Liu contributed equally to this work and shared first authorship. Qian Zeng: Experimentation, Data curation, Writing - original draft. Yina Sun, Mengzhen Lei: Sample collection, Writing - original draft. Zihan Liu: Method optimization. Xijing Yan: Mechanistic interpretation. Rong Li, Lijun Zhang: Writing - review & editing. Jun Zheng: Conceptualization, Experimental design guidance, Manuscript re-view. Jiandong Zha: Project administration. Xiaoling Guan: Materials provision. Jia Yao: Supervision, Final manuscript approval. Funding resource: Rong Li and Jun Zheng.

Data availability statement

The data supporting this study’s findings are available from the corresponding author upon reasonable request.

Declaration of competing interest

The authors declare no conflicts of interest related to this study.

Acknowledgements

This study was supported by Natural Science Foundation of Guangdong Province (Grant No. 2024A1515011662) and National Natural Science Foundation of China (Grant No. 82470666).

References

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

[1]	Ribatti D, Tamma R, Annese T. The role of vascular niche and endothelial cells in organogenesis and regeneration. Exp Cell Res. 2021; 398:112398. https://doi.org/10.1016/j.yexcr.2020.112398.

[2]	Bryan-Brown CW. Blood flow to organs: parameters for function and survival in critical illness. Crit Care Med. 1988; 16:170-178.

[3]	Xu H, Qiu X, Wang Z, et al. Role of the portal system in liver regeneration: from molecular mechanisms to clinical management. Liver Res. 2024; 8:1-10. https://doi.org/10.1016/j.livres.2024.01.002.

[4]	Liu J, Man K. Mechanistic insight and clinical implications of ischemia/reper-fusion injury post liver transplantation. Cell Mol Gastroenterol Hepatol. 2023; 15:1463-1474. https://doi.org/10.1016/j.jcmgh.2023.03.003.

[5]	Zhang B, Zhang B, Zhang Z, et al. 42,573 cases of hepatectomy in China: a multicenter retrospective investigation. Sci China Life Sci. 2018; 61:660-670. https://doi.org/10.1007/s11427-017-9259-9.

[6]	Hadian K, Stockwell BR. SnapShot: ferroptosis. Cell. 2020;181:1188- 1188 (e1). https://doi.org/10.1016/j.cell.2020.04.039.

[7]

Liu C, Qin M, Jiang L, Shan J, Sun Y. Mitochondria-targetable cyclometalated iridium(III) complex-based luminescence probe for monitoring and assessing treatment response of ferroptosis-mediated hepatic ischemia-reperfusion injury. Inorg Chem. 2024; 63:21627-21636. https://doi.org/10.1021/acs.inorgchem.4c03170.

[8]	Li R, Yan X, Xiao C, et al. FTO deficiency in older livers exacerbates ferroptosis during ischaemia/reperfusion injury by upregulating ACSL4 and TFRC. Nat Commun. 2024; 15:4760. https://doi.org/10.1038/s41467-024-49202-3.

[9]	Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012; 149:1060-1072. https://doi.org/10.1016/j.cell.2012.03.042.

[10]	Li Y, Du Y, Zhou Y, et al. Iron and copper: critical executioners of ferroptosis, cuproptosis and other forms of cell death. Cell Commun Signal. 2023; 21:327. https://doi.org/10.1186/s12964-023-01267-1.

[11]	Stockwell BR, Friedmann Angeli JP, Bayir H, et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell. 2017; 171: 273-285. https://doi.org/10.1016/j.cell.2017.09.021.

[12]	Yang WS, SriRamaratnam R, Welsch ME, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014; 156:317-331. https://doi.org/10.1016/j.cell.2013.12.010.

[13]	Xue Q, Yan D, Chen X, et al. Copper-dependent autophagic degradation of GPX4 drives ferroptosis. Autophagy. 2023; 19:1982-1996. https://doi.org/10.1080/15548627.2023.2165323.

[14]	Freese R, Lysne V. Niacin - a scoping review for nordic nutrition recommen-dations 2023. Food Nutr Res. 2023; 67. https://doi.org/10.29219/fnr.v67.10299,10.29219/fnr.v67.10299.

[15]	Pantanali CA, Rocha-Santos V, Kubrusly MS, Castro IA, Carneiro-D’Albuquerque LA, Galv-ao FH. The protective effect of nutraceuticals on he-patic ischemia-reperfusion injury in Wistar rats. Int J Mol Sci. 2023; 24:10264. https://doi.org/10.3390/ijms241210264.

[16]	Tian Y, Wang J, Wang W, et al. Mesenchymal stem cells improve mouse non-heart-beating liver graft survival by inhibiting Kupffer cell apoptosis via TLR4-ERK1/2-Fas/FasL-caspase 3 pathway regulation. Stem Cell Res Ther. 2016; 7:157. https://doi.org/10.1186/s13287-016-0416-y.

[17]	Zhang C, Liu X, Jin S, Chen Y, Guo R. Ferroptosis in cancer therapy: a novel approach to reversing drug resistance. Mol Cancer. 2022; 21:47. https://doi.org/10.1186/s12943-022-01530-y.

[18]	Trueblood NA, Ramasamy R, Wang LF, Schaefer S. Niacin protects the isolated heart from ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol. 2000;279:H764-H771. https://doi.org/10.1152/ajpheart.2000.279.2.H764.

[19]	Tai ST, Fu YH, Yang YC, Wang JJ.Niacin ameliorates kidney warm ischemia and reperfusion injury-induced ventricular dysfunction and oxidative stress and disturbance in mitochondrial metabolism in rats. Transplant Proc. 2015; 47: 1079-1082. https://doi.org/10.1016/j.transproceed.2014.11.057.

[20]	Wu Wu Y, Tan HWS, Lin JY, Shen HM, Wang H, Lu G. Molecular mechanisms of autophagy and implications in liver diseases. Liver Res. 2023; 7:56-70. https://doi.org/10.1016/j.livres.2023.02.002.

[21]	Mizushima N, Yoshimori T, Levine B. Methods in mammalian autophagy research. Cell. 2010; 140:313-326. https://doi.org/10.1016/j.cell.2010.01.028.

[22]	Scarpulla RC. Transcriptional paradigms in mammalian mitochondrial biogenesis and function. Physiol Rev. 2008; 88:611-638. https://doi.org/10.1152/physrev.00025.2007.

[23]	Lin J, Wu PH, Tarr PT, et al. Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1alpha null mice. Cell. 2004; 119:121-135. https://doi.org/10.1016/j.cell.2004.09.013.

[24]	Abudu YP, Mouilleron S, Tooze SA, Lamark T, Johansen T. SAMM50 is a re-ceptor for basal piecemeal mitophagy and acts with SQSTM1/p62 in OXPHOS-induced mitophagy. Autophagy. 2021; 17:2656-2658. https://doi.org/10.1080/15548627.2021.1953846.

[25]	Wang Y, Wu N, Li J, et al. The interplay between autophagy and ferroptosis presents a novel conceptual therapeutic framework for neuroendocrine prostate cancer. Pharmacol Res. 2024; 203:107162. https://doi.org/10.1016/j.phrs.2024.107162.

[26]	Barzegari A, Nouri M, Gueguen V, Saeedi N, Pavon-Djavid G, Omidi Y. Mito-chondria-targeted antioxidant mito-TEMPO alleviate oxidative stress induced by antimycin A in human mesenchymal stem cells. J Cell Physiol. 2020; 235: 5628-5636. https://doi.org/10.1002/jcp.29495.

[27]	Cheng J, Xu T, Xun C, et al. Carnosic acid protects against ferroptosis in PC 12 cells exposed to erastin through activation of Nrf2 pathway. Life Sci. 2021; 266: 118905. https://doi.org/10.1016/j.lfs.2020.118905.

[28]	Da Dalt L, Moregola A, Svecla M, et al. The inhibition of inner mitochondrial fusion in hepatocytes reduces non-alcoholic fatty liver and improves meta-bolic profile during obesity by modulating bile acid conjugation. Cardiovasc Res. 2024; 119:2917-2929. https://doi.org/10.1093/cvr/cvad169.

[29]	Suzuki S, Toledo-Pereyra LH, Rodriguez FJ, Cejalvo D. Neutrophil infiltration as an important factor in liver ischemia and reperfusion injury. Modulating ef-fects of FK506 and cyclosporine. Transplantation. 1993; 55:1265-1272. https://doi.org/10.1097/00007890-199306000-00011.

[30]	Maremonti F, Tonnus W, Gavali S, et al. Ferroptosis-based advanced therapies as treatment approaches for metabolic and cardiovascular diseases. Cell Death Differ. 2024; 31:1104-1112. https://doi.org/10.1038/s41418-024-01350-1.

[31]	Zhao H, Mao H. ERRFI 1 exacerbates hepatic ischemia reperfusion injury by promoting hepatocyte apoptosis and ferroptosis in a GRB2-dependent manner. Mol Med. 2024; 30:82. https://doi.org/10.1186/s10020-024-00837-4.

[32]	Mao XL, Cai Y, Chen YH, et al. Novel targets and therapeutic strategies to protect against hepatic ischemia reperfusion injury. Front Med (Lausanne). 2022; 8:757336. https://doi.org/10.3389/fmed.2021.757336.

[33]	Liu J, Luo R, Zhang Y, Li X. Current status and perspective on molecular targets and therapeutic intervention strategy in hepatic ischemia-reperfusion injury. Clin Mol Hepatol. 2024; 30:585-619. https://doi.org/10.3350/cmh.2024.0222.

[34]	Zou L, Liang B, Gao Y, et al. Nicotinic acid riboside regulates Nrf-2/P62-Related oxidative stress and autophagy to attenuate doxorubicin-induced car-diomyocyte injury. BioMed Res Int. 2022; 2022:6293329. https://doi.org/10.1155/2022/6293329.

[35]	Bugger H, Pfeil K. Mitochondrial ROS in myocardial ischemia reperfusion and remodeling. Biochim Biophys Acta Mol Basis Dis. 2020; 1866:165768. https://doi.org/10.1016/j.bbadis.2020.165768.

[36]	Hu C, Xu Q, Shen J, Wang Y. Clinical and genetic characteristics of mito-chondrial encephalopathy due to FOXRED1 mutations: two Chinese case re-ports and a review of the literature. Front Neurol. 2021; 12:633397. https://doi.org/10.3389/fneur.2021.633397.

[37]	Endale HT, Tesfaye W, Mengstie TA. ROS induced lipid peroxidation and their role in ferroptosis. Front Cell Dev Biol. 2023; 11:1226044. https://doi.org/10.3389/fcell.2023.1226044.

[38]	Sun Z, Liu L, Liang H, Zhang L. Nicotinamide mononucleotide induces auto-phagy and ferroptosis via AMPK/mTOR pathway in hepatocellular carcinoma. Mol Carcinog. 2024; 63:577-588. https://doi.org/10.1002/mc.23673.

[39]	Lee J, Woo H, Kang H, Park YK, Lee JY. Nicotinamide riboside targets mito-chondrial unfolded protein response to reduce alcohol-induced damage in Kupffer cells. J Pathol. 2025; 265:110-122. https://doi.org/10.1002/path.6372.

[40]	Deane CS, Willis CRG, Gallagher IJ, et al. Nicotinic acid improves mitochondrial function and associated transcriptional pathways in older inactive males. Transl Exerc Biomed. 2024; 1:277-294. https://doi.org/10.1515/teb-2024-0030.

[41]	Xu B, Zhang P, Tang X, et al. Metabolic rewiring of Kynurenine pathway during hepatic ischemia-reperfusion injury exacerbates liver damage by impairing NAD homeostasis. Adv Sci (Weinh). 2022; 9:e2204697. https://doi.org/10.1002/advs.202204697.

[42]	Abu Shelbayeh O, Arroum T, Morris S, Busch KB. PGC-1α is a master regulator of mitochondrial lifecycle and ROS stress response. Antioxidants (Basel). 2023; 12:1075. https://doi.org/10.3390/antiox12051075.

[43]	Rogina B, Tissenbaum HA. SIRT1, resveratrol and aging. Front Genet. 2024; 15: 1393181. https://doi.org/10.3389/fgene.2024.1393181.

[44]	Li J, Yang D, Li Z, et al. PINK1/Parkin-mediated mitophagy in neurodegener-ative diseases. Ageing Res Rev. 2023; 84:101817. https://doi.org/10.1016/j.arr.2022.101817.

[45]	Baines CP, Kaiser RA, Purcell NH, et al. Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature. 2005; 434: 658-662. https://doi.org/10.1038/nature03434.

[46]	Chen J, Li X, Ge C, Min J, Wang F. The multifaceted role of ferroptosis in liver disease. Cell Death Differ. 2022; 29:467-480. https://doi.org/10.1038/s41418-022-00941-0.

[47]	Oltean M. Ischemic preconditioning in liver transplantation: lost in trans-lation? J Invest Surg. 2022; 35:910-911. https://doi.org/10.1080/08941939.2021.1943574.

[48]	Stojic J, Kukla M, Grgurevic I. The intestinal microbiota in the development of chronic liver disease: current status. Diagnostics (Basel). 2023; 13:2960. https://doi.org/10.3390/diagnostics13182960.

[49]	Sahu A, Jeon J, Lee MS, Yang HS, Tae G. Nanozyme impregnated mesenchymal stem cells for hepatic ischemia-reperfusion injury alleviation. ACS Appl Mater Interfaces. 2021; 13:25649-25662. https://doi.org/10.1021/acsami.1c03027.