Lysophosphatidic Acid Promotes Colitis-Associated Intestinal Fibrosis by Suppressing Autophagy Via LPAR3/ AMPK/mTOR Pathway

Intestinal fibrosis, which causes bowel stricture and obstruction, is a serious complication of Crohn’s disease (CD). Lysophosphatidic acid (LPA), a bioactive lipid mediator, exerts pro-fibrotic effects in various chronic diseases through its six cognate receptors (LPAR1-6). While both elevated LPA levels and impaired autophagy have been observed in CD patients, their specific contributions to intestinal fibrogenesis remain poorly understood. In this study, the plasma levels of LPA were measured in CD patients with or without intestinal fibrosis by ELISA. Fibrotic and non-fibrotic intestinal tissues were obtained from patients with CD undergoing surgical resection. Masson's staining was performed to evaluate the fibrosis index score. The mRNA expression of LPARs and collagen was detected in intestinal tissues from CD patients with or without intestinal fibrosis by reverse-transcriptase polymerase chain reaction (qRT-PCR). A DSS-induced chronic colitis model with intestinal fibrosis was established in C57BL/6J mice. These mice were administered either an intraperitoneal injection of the LPAR3 antagonist (Ki16425) or vehicle control, and colonic fibrosis indices were subsequently evaluated. Human intestinal fibroblasts (HIFs) were isolated from surgically resected fibrotic intestines of CD patients and the effects of LPA on autophagy, activation, proliferation, and migration of HIFs were determined. Clinical analyses revealed significantly elevated plasma LPA levels and increased LPAR3 expression in fibrotic intestinal tissues of CD patients compared with non-fibrotic controls. Similarly, mice with DSS-induced chronic colitis exhibited elevated plasma LPA levels and increased LPAR3 expression; pharmacological inhibition of LPAR3 attenuated both intestinal inflammation and fibrosis. Mechanistically, in vitro experiments demonstrated that LPA promotes HIF migration, activation and proliferation through LPAR3-dependent suppression of autophagy via the AMPK-mTOR pathway. These pro-fibrotic effects were reversed by LPAR3 knockdown and pharmacological interventions at multiple levels—including LPAR3 antagonism (Ki16425), AMPK activation (A-769662) or mTOR inhibition (rapamycin). Our findings establish a novel LPA-LPAR3-AMPK-mTOR signaling axis that drives intestinal fibrosis by suppressing autophagy in HIFs. This pathway represents a promising therapeutic target for preventing fibrosis progression in CD.