Colchicine alleviates severe acute pancreatitis in rats by inhibiting acinar cell ferroptosis via LCN2/MAPK/ERK signaling axis.

Colchicine (COL) is known to ameliorate severe acute pancreatitis (SAP), yet the precise molecular mechanisms remain elusive. This study integrates bioinformatics with in vivo experimentation to elucidate the mechanism by which COL attenuates SAP. An SAP rat model was established via sodium taurocholate injection. Key therapeutic targets were screened using transcriptomics and network pharmacology. Mechanistic validation utilized AAV-mediated lipocalin-2 (LCN2) overexpression, the ferroptosis inhibitor ferrostatin-1 (Fer-1), and the ERK inhibitor PD98059. COL treatment significantly ameliorated pancreatic pathological injury, inflammatory cell infiltration, and cytokine release. LCN2 was identified as a pivotal target markedly upregulated in SAP but downregulated by COL. Crucially, LCN2 overexpression reversed COL's therapeutic benefits and restored ferroptosis markers (COX2, Fe2+, ROS) while suppressing anti-ferroptotic indices. Notably, this reversal was effectively abrogated by co-treatment with either Fer-1 or PD98059, confirming the involvement of the MAPK/ERK pathway. This study is the first to elucidate that COL inhibits ferroptosis in pancreatic acinar cells by downregulating LCN2 and subsequently suppressing the LCN2/MAPK/ERK signaling axis. These findings provide a novel molecular basis for COL and highlight a potential target for therapeutic intervention in SAP.