鸢尾素:一种调控铁死亡与焦亡的新型肌因子

doi:10.3969/j.issn.1674-490X.2026.04.002

摘要/Abstract

摘要： 鸢尾素是一种主要由骨骼肌分泌的新型肌因子,具有诱导白色脂肪褐变、维持糖脂代谢稳态及骨保护等多种生物学功能。鸢尾素还参与调控多种疾病的病理过程,尤其在细胞程序性死亡中的作用备受关注。铁死亡和焦亡是两种新型程序性细胞死亡方式,分别以铁依赖性脂质过氧化和炎症小体激活为特征,与代谢性疾病、炎症损伤及肿瘤等的发生发展密切相关。系统综述鸢尾素在脓毒症、糖尿病相关疾病、缺血再灌注损伤、骨质疏松症及肿瘤等多种病理状态下调控铁死亡与焦亡的作用及分子机制,并探讨其作为潜在治疗靶点的前景与挑战,以期为后续研究提供理论依据。

关键词: 鸢尾素, 程序性细胞死亡, 铁死亡, 焦亡

Abstract: Irisin is a novel myokine primarily secreted by skeletal muscle, exhibiting multiple biological functions including the induction of white adipose tissue browning, maintenance of glucose and lipid homeostasis, and bone protection. Irisin is also involved in regulating the pathological processes of various diseases, with particular attention drawn to its role in programmed cell death. Ferroptosis and pyroptosis are two emerging forms of programmed cell death, characterized by iron-dependent lipid peroxidation and inflammasome activation respectively, and are closely associated with the onset and progression of metabolic diseases, inflammatory injuries, and tumors. This article systematically reviews the role and molecular mechanisms of irisin in regulating ferroptosis and pyroptosis under various pathological conditions, including sepsis, diabetes-related diseases, ischemia-reperfusion injury, osteoporosis and cancer. Furthermore, it discusses the prospects and challenges of irisin as a potential therapeutic target, aiming to provide a theoretical basis for future research.

Key words: irisin, programmed cell death, ferroptosis, pyroptosis

中图分类号:

R363
R34

罗长勤,刘佳林,范丽苑. 鸢尾素:一种调控铁死亡与焦亡的新型肌因子[J]. 医学研究与教育, 2026, 43(4): 14-27.

Luo Changqin, Liu Jialin, Fan Liyuan. Irisin: a novel myokine regulating ferroptosis and pyroptosis[J]. Journal of Hebei Medical College for Continuing Education, 2026, 43(4): 14-27.

参考文献

[1] Pesce M, Ballerini P, Paolucci T, et al. Irisin and autophagy: first update[J]. IJMS, 2020, 21(20): 7587. DOI: 10.3390/ijms21207587.
[2] Boström P, Wu J, Jedrychowski M P, et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis[J]. Nature, 2012, 481(7382): 463-468. DOI: 10.1038/nature10777.
[3] Askari H, Rajani S F, Poorebrahim M, et al. A glance at the therapeutic potential of irisin against diseases involving inflammation, oxidative stress, and apoptosis: an introductory review[J]. Pharmacol Res, 2018, 129: 44-55. DOI: 10.1016/j.phrs.2018.01.012.
[4] Hu X L, Wang Z, Wang W, et al. Irisin as an agent for protecting against osteoporosis: a review of the current mechanisms and pathways[J]. J Adv Res, 2024, 62: 175-186. DOI: 10.1016/j.jare.2023.09.001.
[5] Tu Y M, Liu J Z, Kong D Q, et al. Irisin drives macrophage anti-inflammatory differentiation via JAK2-STAT6-dependent activation of PPARγ and Nrf2 signaling[J]. Free Radic Biol Med, 2023, 201: 98-110. DOI: 10.1016/j.freeradbiomed.2023.03.014.
[6] Li G Y, Qin H, Zhou M J, et al. Knockdown of SIRT3 perturbs protective effects of irisin against bone loss in diabetes and periodontitis[J]. Free Radic Biol Med, 2023, 200: 11-25. DOI: 10.1016/j.freeradbiomed.2023.02.023.
[7] Peng F, Liao M R, Qin R, et al. Regulated cell death(RCD)in cancer: key pathways and targeted therapies[J]. Sig Transduct Target Ther, 2022, 7(1): 286. DOI: 10.1038/s41392-022-01110-y.
[8] Bedoui S, Herold M J, Strasser A. Emerging connectivity of programmed cell death pathways and its physiological implications[J]. Nat Rev Mol Cell Biol, 2020, 21(11): 678-695. DOI: 10.1038/s41580-020-0270-8.
[9] Miyata T, Nagy L E. Programmed cell death in alcohol-associated liver disease[J]. Clin Mol Hepatol, 2020, 26(4): 618-625. DOI: 10.3350/cmh.2020.0142.
[10] Qian S E, Long Y, Tan G L, et al. Programmed cell death: molecular mechanisms, biological functions, diseases, and therapeutic targets[J]. Med Comm, 2024, 5(12): e70024. DOI: 10.1002/mco2.70024.
[11] Jiang X J, Stockwell B R, Conrad M. Ferroptosis: mechanisms, biology and role in disease[J]. Nat Rev Mol Cell Biol, 2021, 22(4): 266-282. DOI: 10.1038/s41580-020-00324-8.
[12] Ru Q, Li Y S, Chen L, et al. Iron homeostasis and ferroptosis in human diseases: mechanisms and therapeutic prospects[J]. Sig Transduct Target Ther, 2024, 9(1): 271. DOI: 10.1038/s41392-024-01969-z.
[13] Chen X, Li J B, Kang R, et al. Ferroptosis: machinery and regulation[J]. Autophagy, 2021, 17(9): 2054-2081. DOI: 10.1080/15548627.2020.1810918.
[14] Kerins M J, Ooi A. The roles of NRF2 in modulating cellular iron homeostasis[J]. Antioxid Redox Signal, 2018, 29(17): 1756-1773. DOI: 10.1089/ars.2017.7176.
[15] LaRock D L, Johnson A F, Wilde S, et al. Group A Streptococcus induces GSDMA-dependent pyroptosis in keratinocytes[J]. Nature, 2022, 605(7910): 527-531. DOI: 10.1038/s41586-022-04717-x.
[16] Yu G, Choi Y K, Lee S. Inflammasome diversity: exploring novel frontiers in the innate immune response[J]. Trends Immunol, 2024, 45(4): 248-258. DOI: 10.1016/j.it.2024.02.004.
[17] Zhang H W, Liao J, Jin L T, et al. NLRP3 inflammasome involves in the pathophysiology of sepsis-induced myocardial dysfunction by multiple mechanisms[J]. Biomed Pharmacother, 2023, 167: 115497. DOI: 10.1016/j.biopha.2023.115497.
[18] Kayagaki N, Webster J D, Newton K. Control of cell death in health and disease[J]. Annu Rev Pathol, 2024, 19: 157-180. DOI: 10.1146/annurev-pathmechdis-051022-014433.
[19] Karampela I, Vallianou N G, Tsilingiris D, et al. Alterations of the adipo-myokine irisin in sepsis and septic shock: diagnostic and prognostic implications[J]. Biomolecules, 2024, 14(3): 291. DOI: 10.3390/biom14030291.
[20] Wei S S, Bi J B, Yang L F, et al. Serum irisin levels are decreased in patients with sepsis, and exogenous irisin suppresses ferroptosis in the liver of septic mice[J]. Clin Transl Med, 2020, 10(5): e173. DOI: 10.1002/ctm2.173.
[21] Wang J, Zhu Q, Wang Y, et al. Irisin protects against sepsis-associated encephalopathy by suppressing ferroptosis via activation of the Nrf2/GPX4 signal axis[J]. Free Radic Biol Med, 2022, 187: 171-184. DOI: 10.1016/j.freeradbiomed.2022.05.023.
[22] Gui S H, Zhu C C, Lu Y F. Fibronectin type Ⅲ domain containing protein 5/irisin alleviated sepsis-induced acute kidney injury by abating ferroptosis through the adenosine 5'-monophosphate-activated protein kinase/nuclear factor erythroid-2-related factor 2 signaling pathway[J]. Cytojournal, 2024, 21: 54. DOI: 10.25259/cytojournal_62_2024.
[23] Zhang Q Y, Yang X, Peng M, et al. Post-treatment with irisin attenuates acute kidney injury in sepsis mice through anti-ferroptosis via the SIRT1/Nrf2 pathway[J]. Front Pharmacol, 2022, 13: 857067. DOI: 10.3389/fphar.2022.857067.
[24] Vasudevan S O, Behl B, Rathinam V A. Pyroptosis-induced inflammation and tissue damage[J]. Semin Immunol, 2023, 69: 101781. DOI: 10.1016/j.smim.2023.101781.
[25] Li Q, Zhang M M, Zhao Y, et al. Irisin protects against LPS-stressed cardiac damage through inhibiting inflammation, apoptosis, and pyroptosis[J]. Shock, 2021, 56(6): 1009-1018. DOI: 10.1097/SHK.0000000000001775.
[26] Li Q, Tan Y, Chen S N, et al. Irisin alleviates LPS-induced liver injury and inflammation through inhibition of NLRP3 inflammasome and NF-κB signaling[J]. J Recept Signal Transduct, 2021, 41(3): 294-303. DOI: 10.1080/10799893.2020.1808675.
[27] Han Z X, Ma J, Han Y, et al. Irisin attenuates acute lung injury by suppressing the pyroptosis of alveolar macrophages[J]. Int J Mol Med, 2023, 51(4): 32. DOI: 10.3892/ijmm.2023.5235.
[28] Xiong X, Lu L H, Wang Z Y, et al. Irisin attenuates sepsis-induced cardiac dysfunction by attenuating inflammation-induced pyroptosis through a mitochondrial ubiquitin ligase-dependent mechanism[J]. Biomed Pharmacother, 2022, 152: 113199. DOI: 10.1016/j.biopha.2022.113199.
[29] Shrikanth C B, Nandini C D. AMPK in microvascular complications of diabetes and the beneficial effects of AMPK activators from plants[J]. Phytomedicine, 2020, 73: 152808. DOI: 10.1016/j.phymed.2018.12.031.
[30] Tang Y J, Zhang Z, Yan T, et al. Irisin attenuates type 1 diabetic cardiomyopathy by anti-ferroptosis via SIRT1-mediated deacetylation of p53[J]. Cardiovasc Diabetol, 2024, 23(1): 116. DOI: 10.1186/s12933-024-02183-5.
[31] Ye H M, Guo J, Wang X Y, et al. Irisin protects against diabetic cardiomyopathy by suppressing ferroptosis[J]. Drug Dev Res, 2025, 86(4): e70077. DOI: 10.1002/ddr.70077.
[32] Lu L H, Shao Y L, Xiong X, et al. Irisin improves diabetic cardiomyopathy-induced cardiac remodeling by regulating GSDMD-mediated pyroptosis through MITOL/STING signaling[J]. Biomed Pharmacother, 2024, 171: 116007. DOI: 10.1016/j.biopha.2023.116007.
[33] Li T R, Yang J J, Tan A J, et al. Irisin suppresses pancreatic β cell pyroptosis in T2DM by inhibiting the NLRP3-GSDMD pathway and activating the Nrf2-TrX/TXNIP signaling axis[J]. Diabetol Metab Syndr, 2023, 15(1): 239. DOI: 10.1186/s13098-023-01216-5.
[34] Yang J J, Tan A J, Li T R, et al. Irisin alleviates the pyroptosis of β cells in T2DM by inhibiting NLRP3 inflammasome through regulating miR-19b-3p/SOCS3/STAT3 axis mediated autophagy[J]. IUBMB Life, 2024, 76(12): 1264-1278. DOI:10.1002/iub.2907.
[35] Tan A J, Li T R, Yang J J, et al. Irisin attenuates pyroptosis in high glucose-induced pancreatic beta cells via the miR-133a-3p/FOXO1 axis[J]. Endokrynol Pol, 2023, 74(3): 277-284. DOI: 10.5603/EP.a2023.0035.
[36] Tan A J, Li T R, Yang J J, et al. Irisin regulates integrin αvβ5/FAK/ERK to inhibit neutrophil extracellular traps formation and reduce pancreatic beta-cells pyroptosis in type 2 diabetes mellitus[J]. Diabetol Metab Syndr, 2025, 17(1): 279. DOI: 10.1186/s13098-025-01852-z.
[37] Yang L L, Zhou X H, Heng T, et al. FNDC5/Irisin mitigates high glucose-induced neurotoxicity in HT22 cell via ferroptosis[J]. BST, 2024, 18(5): 465-475. DOI: 10.5582/bst.2024.01249.
[38] Wang D, Zhu F R, Shao M M, et al. Irisin attenuates tubular epithelial ferroptosis in diabetic kidney disease by inhibiting the HMGB1/Nrf2/GPX4 pathway[J]. Naunyn Schmiedebergs Arch Pharmacol, 2026, 399(3): 4247-4265. DOI: 10.1007/s00210-025-04681-z.
[39] Yuan Y, Liu Y X, Sun M Y, et al. Aggravated renal fibrosis is positively associated with the activation of HMGB1-TLR2/4 signaling in STZ-induced diabetic mice[J]. Open Life Sci, 2022, 17(1): 1451-1461. DOI: 10.1515/biol-2022-0506.
[40] Behera J, Ison J, Voor M J, et al. Exercise-linked skeletal irisin ameliorates diabetes-associated osteoporosis by inhibiting the oxidative damage-dependent miR-150-FNDC5/pyroptosis axis[J]. Diabetes, 2022, 71(12): 2777-2792. DOI: 10.2337/db21-0573.
[41] Land W G. The role of postischemic reperfusion injury and other nonantigen-dependent inflammatory pathways in transplantation[J]. Transplantation, 2005, 79(5): 505-514. DOI: 10.1097/01.tp.0000153160.82975.86.
[42] Zhang J, Bi J B, Ren Y F, et al. Involvement of GPX4 in irisin's protection against ischemia reperfusion-induced acute kidney injury[J]. J Cell Physiol, 2021, 236(2): 931-945. DOI: 10.1002/jcp.29903.
[43] Wang Y, Dong Z, Zhang Z Z, et al. Postconditioning with irisin attenuates lung ischemia/reperfusion injury by suppressing ferroptosis via induction of the Nrf2/HO-1 signal axis[J]. Oxid Med Cell Longev, 2022, 2022: 9911167. DOI: 10.1155/2022/9911167.
[44] Fang C N, Huang L, Gu J Y, et al. Exosomal irisin from FNDC5-engineered BMSCs improves ischemic stroke via inhibiting YAP/EGR1/ACSL4-mediated ferroptosis[J]. Exp Neurol, 2025, 387: 115172. DOI: 10.1016/j.expneurol.2025.115172.
[45] Ho M Y, Wang C Y. Role of irisin in myocardial infarction, heart failure, and cardiac hypertrophy[J]. Cells, 2021, 10(8): 2103. DOI: 10.3390/cells10082103.
[46] Cao G Y, Yang C, Jin Z T, et al. FNDC5/irisin reduces ferroptosis and improves mitochondrial dysfunction in hypoxic cardiomyocytes by Nrf2/HO-1 axis[J]. Cell Biol Int, 2022, 46(5): 723-736. DOI: 10.1002/cbin.11763.
[47] Jin L, Piao Z H. Irisin protects against cardiac injury by inhibiting NLRP3 inflammasome-mediated pyroptosis during remodeling after infarction[J]. Int Immunopharmacol, 2024, 130: 111714. DOI: 10.1016/j.intimp.2024.111714.
[48] Yue R C, Zheng Z Y, Luo Y, et al. NLRP3-mediated pyroptosis aggravates pressure overload-induced cardiac hypertrophy, fibrosis, and dysfunction in mice: cardioprotective role of irisin[J]. Cell Death Discov, 2021, 7(1): 50. DOI: 10.1038/s41420-021-00434-y.
[49] Jia S S, Yang Y, Bai Y S, et al. Mechanical stimulation protects against chondrocyte pyroptosis through irisin-induced suppression of PI3K/Akt/NF-κB signal pathway in osteoarthritis[J]. Front Cell Dev Biol, 2022, 10: 797855. DOI: 10.3389/fcell.2022.797855.
[50] Assem M, Lando M, Grissi M, et al. The impact of uremic toxins on cerebrovascular and cognitive disorders[J]. Toxins, 2018, 10(7): 303. DOI: 10.3390/toxins10070303.
[51] Pang Q, Wang P W, Pan Y J, et al. Irisin protects against vascular calcification by activating autophagy and inhibiting NLRP3-mediated vascular smooth muscle cell pyroptosis in chronic kidney disease[J]. Cell Death Dis, 2022, 13(3): 283. DOI: 10.1038/s41419-022-04735-7.
[52] Xu W J, Wang P W, Zhu X W, et al. Irisin targets the HK1-glycolysis-NLRP3 pyroptosis axis to prevent chronic kidney disease-associated vascular calcification[J]. Ren Fail, 2025, 47(1): 2610545. DOI: 10.1080/0886022X.2025.2610545.
[53] Zhou T, Wang S Y, Pan Y J, et al. Irisin ameliorated skeletal muscle atrophy by inhibiting fatty acid oxidation and pyroptosis induced by palmitic acid in chronic kidney disease[J]. Kidney Blood Press Res, 2023, 48(1): 628-641. DOI: 10.1159/000533926.
[54] Wang P X, Pang Q, Zhang A H. Keto acids attenuate skeletal muscle atrophy in chronic kidney disease via inhibiting pyroptosis and upregulating irisin precursor FNDC5 expression[J]. Calcif Tissue Int, 2025, 116(1): 63. DOI: 10.1007/s00223-025-01372-y.
[55] Zhang J L, Dong X T, Pang Q, et al. Irisin alleviates cognitive impairment by inhibiting AhR/NF-κB-NLRP3-mediated pyroptosis of hippocampal neurons in chronic kidney disease[J]. Mediators Inflamm, 2024, 2024: 2662362. DOI: 10.1155/mi/2662362.
[56] Dong Q Q, Han Z Q, Gao M D, et al. FNDC5/irisin ameliorates bone loss of type 1 diabetes by suppressing endoplasmic reticulum stress-mediated ferroptosis[J]. J Orthop Surg Res, 2024, 19(1): 205. DOI: 10.1186/s13018-024-04701-3.
[57] Tao L, Wang J P, Wang K, et al. Exerkine FNDC5/irisin-enriched exosomes promote proliferation and inhibit ferroptosis of osteoblasts through interaction with Caveolin-1[J]. Aging Cell, 2024, 23(8): e14181. DOI: 10.1111/acel.14181.
[58] Ma Y X, Zheng J C, Liu Y, et al. Irisin ameliorates age-associated skeletal muscle atrophy in mice: potential involvement of iron overload and SIRT1/p53 pathway[J]. J Physiol Biochem, 2025, 81(4): 1199-1209. DOI: 10.1007/s13105-025-01135-1.
[59] Zhang Y L, Zhang Y, Wang D J, et al. Exercise-induced irisin attenuates ferroptosis in polycystic ovary syndrome by modulating the NCOA4-FTH pathway[J]. Biochim Biophys Acta Mol Basis Dis, 2026, 1872(3): 168108. DOI: 10.1016/j.bbadis.2025.168108.
[60] Zhang K, Du Y H, Yang S H, et al. Irisin suppressed the progression of TBI via modulating AMPK/MerTK/autophagy and SYK/ROS/inflammatory signaling[J]. Sci Rep, 2025, 15: 15583. DOI: 10.1038/s41598-025-00066-7.
[61] Yang B C, Leung P S. Irisin is a positive regulator for ferroptosis in pancreatic cancer[J]. Mol Ther Oncolytics, 2020, 18: 457-466. DOI: 10.1016/j.omto.2020.08.002.
[62] Cai H C, Huang C Y, Zhang Z W. Irisin regulates lipid metabolism and ferroptosis in ovarian cancer cells by modulating the ALOX5-5-HETE-PD-L1 axis[J]. Sci Rep, 2026, 16(1): 7223. DOI: 10.1038/s41598-026-36816-4.