Transient receptor potential vanilloid channels in inflammatory bowel diseases: linking inflammation, angiogenesis,...

Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is characterized by chronic relapsing intestinal inflammation driven by complex interactions among immune dysregulation, epithelial barrier disruption, vascular dysfunction, oxidative stress, and gut microbiota imbalance. Despite advances in biologic and small-molecule therapies, a substantial proportion of patients remain refractory to treatment or experience significant adverse effects, underscoring the need for novel mechanistic insights and therapeutic targets. Emerging evidence suggests that the Transient Receptor Potential Vanilloid (TRPV) channel family may represent one of several potential integrative nodes of neurogenic inflammation, immune activation, microvascular dysfunction, epithelial injury, and redox imbalance in IBD. Transient Receptor Potential Vanilloid (TRPV) channels are broadly expressed in intestinal epithelial cells, immune cells, sensory neurons, and vascular endothelial cells, where they regulate Ca²⁺-dependent signaling pathways and reactive oxygen species (ROS)-mediated responses. Functionally, TRPV1 promotes neurogenic inflammation and visceral hypersensitivity through neuropeptide release and inflammatory sensitization; TRPV2 regulates macrophage phagocytosis, chemotaxis, and inflammasome-associated signaling; TRPV3 contributes to epithelial ATP release and barrier-associated purinergic signaling; TRPV4 regulates vascular permeability, VEGF signaling, mechanotransduction, and oxidative stress responses; whereas TRPV5/6 participate in calcium homeostasis, epithelial regeneration, and mucosal repair. Importantly, TRPV-mediated Ca²⁺ influx and ROS signaling form a self-amplifying inflammation-angiogenesis-oxidative stress network that may sustain chronic intestinal injury and therapeutic resistance. This Review systematically summarizes the structural characteristics, cell-specific functions, and pathological roles of TRPV channels in IBD, with particular emphasis on the neuro-immune-vascular-epithelial regulatory axis and the emerging interplay between TRPV signaling, oxidative stress, and pathological angiogenesis. We further discuss current progress and major challenges in TRPV-targeted therapies, including small-molecule modulators, natural compounds, combination strategies, and tissue-specific drug delivery systems. Collectively, these findings raise the possibility that targeting TRPV channels might offer potential avenues for precision medicine and translational intervention in IBD. However, the transition from molecular mechanisms to viable clinical therapeutics remains constrained by current pharmacological limitations.