Pelletierine alleviates alcohol-induced intestinal injury: mediating LOXL2-dependent cGAS-STING signalling in ferroptosis and mitophagy.

ETHNOPHARMACOLOGICAL RELEVANCE Punica granatum L. (pomegranate), a traditional Chinese medicinal plant, has long been used in ethnic medical systems for the treatment of gastrointestinal disorders. Pelletierine (PEL), a piperidine alkaloid isolated from pomegranate root bark, has been reported to exert protective effects against intestinal inflammation.

Aim

OF THE STUDY To examine the protective effects of PEL on alcohol-induced intestinal injury and to clarify the underlying molecular mechanisms.

Materials And Methods

A mouse model of chronic alcohol-induced intestinal injury was established by feeding animals a Lieber-DeCarli liquid diet containing ethanol for 28 days. Separate cohorts of mice received a single tail-vein injection of lentivirus carrying either LOXL2-specific shRNA or control shRNA. Primary intestinal epithelial cells (IECs) were separated from the colonic tissues of untreated mice. In vitro, IECs were treated with PEL and LPS, followed by transfection with LOXL2-specific siRNA to investigate mechanistic role of LOXL2.

Results

PEL dose-dependently attenuated alcohol-induced intestinal injury by improving histopathological alterations, reducing intestinal permeability, and restoring the tight junction proteins. PEL engaged LOXL2 and suppressed the cGAS-STING signaling pathway LOXL2-dependently, as demonstrated by CETSA, SPR, and LOXL2 knockdown experiments. Furthermore, PEL reversed alcohol-induced ferroptosis by upregulating GPX4 and downregulating ACSL4, while restoring impaired mitophagy through activation of PINK1-Parkin pathway.

Conclusions

PEL protects against alcohol-induced intestinal inflammation by suppressing cGAS-STING signaling, modulating ferroptosis, and restoring mitophagy homeostasis. These findings identify LOXL2 as a central pathogenic regulator and indicate that PEL is a potential therapeutic candidate for the treatment of alcohol-induced intestinal injury.