Celastrol Mitigates Acute Pancreatitis Associated Inflammation by Modulating the IL-34/CSF-1R Axis and Suppressing NF-κB/ERK Signaling.

Background: Acute pancreatitis (AP) is characterized by early acinar injury followed by rapid inflammatory amplification, yet the upstream molecular triggers linking tissue stress to cytokine escalation remain incompletely defined. Interleukin-34 (IL-34), a ligand of colony-stimulating factor-1 receptor (CSF-1R), regulates inflammatory signaling, but its role in AP has not been elucidated. Celastrol is a bioactive triterpenoid with established anti-inflammatory properties; however, whether it modulates IL-34-associated signaling in AP remains unclear. Methods: Experimental AP was induced in rats by retrograde sodium taurocholate infusion. Celastrol (6 mg/kg, i.p.) was administered 1 h prior to AP induction. In vitro, caerulein-stimulated AR42J acinar cells and IL-34 overexpressing cells were employed to evaluate functional relevance. ERK/NF-κB activation and inflammatory mediator production were assessed by Western blotting, ELISA, and immunofluorescence. Molecular docking was performed as an exploratory structural analysis of celastrol and the IL-34/CSF-1R complex. Results: Celastrol significantly attenuated pancreatic injury in vivo, reducing serum amylase activity by approximately 34% and improving histological scores (both P < 0.01). IL-34 protein expression was markedly increased in experimental AP (P < 0.001), accompanied by activation of CSF-1R-dependent ERK and NF-κB signaling. IL-34 overexpression enhanced inflammatory outputs, whereas celastrol suppressed IL-34 expression and downstream signaling activation (P < 0.05). Docking analysis suggested structural compatibility between celastrol and IL-34/CSF-1R. Targeting IL-34 signaling may represent a potential therapeutic approach for acute pancreatitis. Conclusion: These findings identify IL-34 as a previously unrecognized contributor to inflammatory amplification in experimental AP. Celastrol treatment was accompanied by reduced IL-34 expression and attenuation of ERK/NF-κB activation. Although further loss of function studies are required to establish direct causality, modulation of IL-34-related signaling may represent a potential therapeutic direction for AP.