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BACKGROUND Ferroptosis is involved in developing inflammatory diseases; yet, its role in acute hypertriglyceridemic pancreatitis (HTGP) remains unclear. AIM To explore whether ferroptosis is involved in the process of HTGP and elucidate its potential mechanisms. METHODS An HTGP mouse model was induced using intraperitoneal injection of P-407 and caerulein (CAE). Then, pancreatic tissues from the model animals were subjected to proteome sequencing analysis. The pathological changes and scores of the pancreas, lung, and kidney were determined using hematoxylin-eosin staining. The levels of serum amylase (AMY), triglyceride, and total cholesterol were measured with an automatic blood cell analyzer. Additionally, the serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β were determined by enzyme linked immunosorbent assay. Malonaldehyde (MDA), glutathione (GSH), and Fe2+ were detected in the pancreas. Finally, immunohistochemistry was performed to assess the expression of ferroptosis-related proteins. RESULTS Proteome sequencing revealed that ferroptosis was involved in the process of HTGP and that NADPH oxidase (NOX) 2 may participate in ferroptosis regulation. Moreover, the levels of serum AMY, TNF-α, IL-6, and IL-1β were significantly increased, MDA and Fe2+ were upregulated, GSH and ferroptosis-related proteins were reduced, and the injury of the pancreas, lung, and kidney were aggravated in the P407 + CAE group compared to CAE and wild type groups (all P < 0.05). Notably, the inhibition of ferroptosis and NOX2 attenuated the pathological damage and the release of TNF-α, IL-6, and IL-1β in the serum of the mice. CONCLUSION Ferroptosis was found to have an important role in HTGP and may be considered a potential target for clinical treatment.