PPARγ signaling pathway: strategies and limitations of natural compounds in the treatment of ulcerative colitis.

Abstract

Ulcerative colitis (UC) is a chronic, relapsing inflammatory bowel disease characterized by persistent inflammatory activation, immune dysregulation, gut microbiota dysbiosis, and damage to the mucosal barrier. Peroxisome proliferator-activated receptor gamma (PPAR&#x3b3;) is a key nuclear receptor involved in maintaining intestinal immunity and mucosal homeostasis. Reduced PPAR&#x3b3; expression or impaired function may weaken its negative regulatory role in pro-inflammatory signaling and disrupt the Th17/Treg balance, macrophage polarization, gut microbiota homeostasis, and barrier integrity, making PPAR&#x3b3; a crucial molecular hub linking multiple pathological processes in UC. Due to their structural diversity and multi-target regulatory properties, natural compounds are attracting increasing attention as potential modulators of PPAR&#x3b3;-related networks. This review systematically summarizes the current preclinical evidence regarding natural compounds that target PPAR&#x3b3; and its associated signaling networks in UC, with particular emphasis on their roles in regulating inflammatory responses, immune cell function, the Th17/Treg balance, the gut microbiota, and mucosal barrier integrity through PPAR&#x3b3;-related pathways (including AMPK, NF-&#x3ba;B, mTOR, SIRT1, MAPK, Nrf2, and STAT). Importantly, the currently available evidence primarily stems from <i>in vitro</i> cellular and <i>in vivo</i> animal studies; therefore, it mainly provides mechanistic and preclinical support rather than evidence of clinical efficacy. Current research is also limited by insufficient evaluation of specific targets, reliance on a limited range of disease models, and inadequate characterization of pharmacokinetic and safety profiles. Future research should prioritize rigorous evaluation of PPAR&#x3b3;-dependent mechanisms, conduct pharmacokinetic and safety assessments, and design rigorous human studies and clinical trials to establish the therapeutic potential of these natural compounds in UC. This review provides a framework for critically evaluating the existing evidence and guiding the development and evaluation of PPAR&#x3b3;-targeting natural compounds for UC.