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 (PPARγ) is a key nuclear receptor involved in maintaining intestinal immunity and mucosal homeostasis. Reduced PPARγ 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 PPARγ 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 PPARγ-related networks. This review systematically summarizes the current preclinical evidence regarding natural compounds that target PPARγ 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 PPARγ-related pathways (including AMPK, NF-κB, mTOR, SIRT1, MAPK, Nrf2, and STAT). Importantly, the currently available evidence primarily stems from in vitro cellular and in vivo 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 PPARγ-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 PPARγ-targeting natural compounds for UC.