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.