Acute pancreatitis (AP) is a common and potentially life-threatening inflammatory disorder of the pancreas. Although it is typically self-limiting, up to 20% of patients may progress to severe acute pancreatitis (SAP), which can lead to systemic inflammatory response syndrome (SIRS), multiple organ dysfunction and failure, affecting organs such as the lungs, kidneys, liver, and heart. Survivors often experience varying degrees of sequelae, including post-pancreatitis diabetes, exocrine pancreatic insufficiency, and chronic pancreatitis. Currently, the primary treatment approaches involve fluid resuscitation and a series of supportive therapies. This low-targeted treatment strategy is a major reason for the persistently high mortality rates associated with AP, particularly SAP. Previous studies have indicated that calcium ions can mediate acinar cell damage and death, as well as influence the unfolded protein response and autophagy, affecting the pathogenesis of pancreatitis. However, our understanding of the mechanisms of acinar parenchymal cell death and other pathogenic factors remains limited, leading to a symptomatic and supportive stage of treatment for AP. Iron death and autophagy are distinct mechanisms of regulated cell death. Iron death is a novel form of cell death triggered by iron-dependent lipid peroxidation, while autophagy is the primary catabolic process through which cells eliminate damaged, defective, or unwanted organelles, along with long-lived proteins and lipids, recycling their components to meet energy demands and biogenetic needs. Both mechanisms have unique characteristics and are interconnected, playing significant roles in AP. This article reviews recent advances in the research on iron death and autophagy in the pathogenesis of AP, providing new insights and regulatory targets for understanding and treating AP, which may facilitate the development of more effective targeted therapies.

1.Mederos MA, Reber HA, Girgis MD, et al. Acute pancreatitis: a review[J]. JAMA, 2021, 325(4): 382-390. DOI: 10.1001/jama.2020.20317.

2.Garg PK, Singh VP. Organ failure due to systemic injury in acute pancreatitis[J]. Gastroenterology, 2019, 156(7): 2008-2023. DOI: 10.1053/j.gastro.2018.12.041.

3.Lee PJ, Papachristou GI. New insights into acute pancreatitis[J]. Nat Rev Gastroenterol Hepatol, 2019, 16(8): 479-496. DOI: 10.1038/s41575-019-0158-2.

4.Gao L, Dong X, Gong W, et al. Acinar cell NLRP3 inflammasome and gasdermin D (GSDMD) activation mediates pyroptosis and systemic inflammation in acute pancreatitis[J]. Br J Pharmacol, 2021, 178(17): 3533-3552. DOI: 10.1111/bph.15499.

5.Sendler M, Van DC, Glaubitz J, et al. NLRP3 inflammasome regulates development of systemic inflammatory response and compensatory anti-inflammatory response syndromes in mice with acute pancreatitis[J]. Gastroenterology, 2020, 158(1): 253-269. e14. DOI: 10.1053/j.gastro.2019.09.040.

6.Kist M, Vucic D. Cell death pathways: intricate connections and disease implications[J]. EMBO J, 2021, 40(5): e106700. DOI: 10.15252/embj.2020106700.

7.Galluzzi L, Vitale I, Aaronson SA, et al. Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018[J]. Cell Death Differ, 2018, 25(3): 486-541. DOI: 10.1038/s41418-017-0012-4.

8.Yue M, Wei J, Chen W, et al. Neurotrophic role of the next-generation probiotic strain l. lactis MG1363-pMG36e-GLP-1 on Parkinson's disease via inhibiting ferroptosis[J]. Nutrients, 2022, 14(22): 4886. DOI: 10.3390/nu14224886.

9.Luo MY, Su JH, Gong SX, et al. Ferroptosis: new dawn for overcoming the cardio-cerebrovascular diseases[J]. Front Cell Dev Biol, 2021, 9: 733908. DOI: 10.3389/fcell.2021.733908.

10.Fan R, Sui J, Dong X, et al. Wedelolactone alleviates acute pancreatitis and associated lung injury via GPX4 mediated suppression of pyroptosis and ferroptosis[J]. Free Radic Biol Med, 2021, 173: 29-40. DOI: 10.1016/j.freeradbiomed.2021.07.009.

11.Zeng F, Nijiati S, Tang L, et al. Ferroptosis detection: from approaches to applications[J]. Angew Chem Int Ed Engl, 2023, 62(35): e202300379. DOI: 10.1002/anie.202300379.

12.Tang D, Chen X, Kang R, et al. Ferroptosis: molecular mechanisms and health implications[J]. Cell Res, 2021, 31(2): 107-125. DOI: 10.1038/s41422-020-00441-1.

13.Liu J, Song XX, Kuang FM, et al. NUPR1 is a critical repressor of ferroptosis[J]. Nature Commun, 2021, 12(1): 647. DOI: 10.1038/s41467-021-20904-2.

14.Arabul M, Celik M, Aslan O, et al. Hepcidin as a predictor of disease severity in acute pancreatitis: a single center prospective study[J]. Hepatogastroenterology, 2013, 60(123): 595-600. DOI: 10.5754/hge12770.

15.Hart PA, Bradley D, Conwell DL, et al. Diabetes following acute pancreatitis[J]. Lancet Gastroenterol Hepatol, 2021, 6(8): 668-675. DOI: 10.1016/S2468-1253(21)00019-4.

16.Jiang X, Stockwell BR, Conrad M, et al. Ferroptosis: mechanisms, biology and role in disease[J]. Nature Rev Mol Cell Biol, 2021,22(4):266-282. DOI: 10.1038/s41580-020-00324-8.

17.Ma DL, Li C, Jiang PL. Inhibition of ferroptosis attenuates acute kidney injury in rats with severe acute pancreatitis[J]. Dig Dis Sci, 2021, 66(2): 483-492. DOI: 10.1007/s10620-020-06225-2.

18.Shi ZH, Wang Y, Ye W, et al. The LipoxinA4 receptor agonist BML-111 ameliorates intestinal disruption following acute pancreatitis through the Nrf2-regulated antioxidant pathway[J]. Free Radic Biol Med, 2021, 163: 379-391. DOI: 10.1016/j.freeradbiomed.2020.12.232.

19.Jeong YK, Kim H. A mini-review on the effect of docosahexaenoic acid (DHA) on cerulein-induced and hypertriglyceridemic acute pancreatitis[J]. Int J Mol Sci, 2017, 18(11). DOI: 10.3390/ijms18112239.

20.Chen WW, Yuan CC, Lu YY, et al. Tanshinone IIA Protects against Acute Pancreatitis in Mice by Inhibiting Oxidative Stress via the Nrf2/ROS Pathway[J]. Oxid Med Cell Longev, 2020, 2020(5390482). DOI: 10.1155/2020/5390482.

21.Mei QX, Deng GY, Huang ZH, et al. Porous COS@SiO(2) nanocomposites ameliorate severe acute pancreatitis and associated lung injury by regulating the Nrf2 signaling pathway in mice[J]. Front Chem, 2020, 8: 720. DOI: 10.3389/fchem.2020.00720.

22.Shin JY, Choi JW, Kim DG, et al. Protective effects of Coenzyme Q10 against acute pancreatitis[J]. Int Immunopharmacol, 2020, 88: 106900. DOI: 10.1016/j.intimp.2020.106900.

23.Li J, Cao F, Yin HL, et al. Ferroptosis: past, present and future[J]. Cell Death Dis, 2020, 11(2): 88. DOI: 10.1038/s41419-020-2298-2.

24.Liu S, Yao S, Yang H, et al. Autophagy: regulator of cell death[J]. Cell Death Dis, 2023, 14(10): 648. DOI: 10.1038/s41419-023-06154-8.

25.Yang Y, Huang QL, Luo C, et al. MicroRNAs in acute pancreatitis: from pathogenesis to novel diagnosis and therapy[J]. J Cell Physiol, 2020, 235(3): 1948-1961. DOI: 10.1002/jcp.29212.

26.Svetlana V, Michael C, Francesca DF, et al. Autophagy, acute pancreatitis and the metamorphoses of a trypsinogen-activating organelle[J]. Cells, 2022, 11(16): 2514. DOI: 10.3390/cells11162514.

27.Padhan RK, Jain S, Agarwal S, et al. Primary and secondary organ failures cause mortality differentially in acute pancreatitis and should be distinguished[J]. Pancreas, 2018, 47(3): 302-307. DOI: 10.1097/MPA.0000000000000998.

28.Habtezion A, Gukovskaya AS, Pandol SJ. Acute pancreatitis: a multifaceted set of organelle and cellular interactions[J]. Gastroenterology, 2019, 156(7): 1941-1950. DOI: 10.1053/j.gastro.2018.11.082.

29.Zhang T, Gan Y, Zhu S. Association between autophagy and acute pancreatitis[J]. Front Gen, 2023, 14: 998035. DOI: 10.3389/fgene.2023.998035.

30.Yuan XH, Wu J, Guo X, et al. Autophagy in acute pancreatitis: organelle interaction and microRNA regulation[J]. Oxid Med Cell Longev, 2021, 2021: 8811935. DOI: 10.1155/2021/8811935.

31.Biczo G, Vegh ET, Shalbueva N, et al. Mitochondrial dysfunction, through impaired autophagy, leads to endoplasmic reticulum stress, deregulated lipid metabolism, and pancreatitis in animal models[J]. Gastroenterology, 2018, 154(3): 689-703. DOI: 10.1053/j.gastro.2017.10.012.

32.Vanasco V, Ropolo A, Grasso A, et al. Mitochondrial dynamics and VMP1-related selective mitophagy in experimental acute pancreatitis[J]. Front Cell Dev Biol, 2021, 9: 640094. DOI: 10.3389/fcell.2021.640094.

33.Zhou WC, Dong S, Chen Z, et al. New challenges for microRNAs in acute pancreatitis: progress and treatment[J]. J Tran Med, 2022, 20(1): 192. DOI: 10.1186/s12967-022-03338-2.

34.Xiang H, Tao X, Xia S, et al. Targeting microRNA function in acute pancreatitis[J]. Front Physiol, 2017, 8: 726. DOI: 10.3389/fphys.2017.00726.

35.Li YH, Liu T, Lai XY, et al. Rational design peptide inhibitors of cyclophilin D as a potential treatment for acute pancreatitis[J]. Medicine (Baltimore), 2023, 102(48): e36188. DOI: 10.1097/MD.0000000000036188.

36.Gao W, Wang X, Zhou Y, et al. Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy[J]. Signal Transduct Target Ther, 2022, 7(1): 196. DOI: 10.1038/s41392-022-01046-3.

37.Liu J, Kuang F, Kroemer G, et al. Autophagy-dependent ferroptosis: machinery and regulation[J]. Cell Chem Biol, 2020, 27(4): 420-435. DOI: 10.1016/j.chembiol.2020.02.005.

38.Yang MH, Chen P, Liu J, et al. Clockophagy is a novel selective autophagy process favoring ferroptosis[J]. Sci Adv, 2019, 5(7): eaaw2238. DOI: 10.1126/sciadv.aaw2238.

39.Yang AL, McNabb-Baltar J. Hypertriglyceridemia and acute pancreatitis[J]. Pancreatology, 2020, 20(5): 795-800. DOI: 10.1016/j.pan.2020.06.005.

40.Szatmary P, Grammatikopoulos T, Cai W, et al. Acute pancreatitis: diagnosis and treatment[J]. Drugs, 2022, 82(12): 1251-1276. DOI: 10.1007/s40265-022-01766-4.

41.Hu ZY, Wang DY, Gong J, et al. MSCs deliver hypoxia-treated mitochondria reprogramming acinar metabolism to alleviate severe acute pancreatitis injury[J]. Adv Sci (Weinheim), 2023, 10(25): e2207691. DOI: 10.1002/advs.202207691.

42.Wang JJ, Xia Y, Cao Y, et al. Evaluating the efficacy and timing of blood purification modalities in early-stage hyperlipidemic acute pancreatitis treatment[J]. Lipids Health Dis, 2023, 22(1): 208. DOI: 10.1186/s12944-023-01968-z.