Thioredoxin-interacting protein in fibrotic diseases: Mechanisms and therapeutic strategies

Thioredoxin-interacting protein (TXNIP) critically regulates cellular redox homeostasis. It drives multi-organ fibrosis by integrating oxidative stress, inflammation, metabolic dysregulation, and autophagic dysfunction. TXNIP contributes to organ-specific fibrotic responses in the liver, kidney, heart, and lung through multiple core signaling pathways, including the NLRP3 inflammasome, TGF-β1/Smad, NF-κB, and mTOR cascades. Notably, TXNIP exhibits cell- and organ-specific dual regulatory characteristics during fibrogenesis, adding further complexity to its mechanistic involvement. In recent years, targeting TXNIP has emerged as a promising strategy in anti-fibrotic research. Clinically relevant small-molecule drugs, natural products and bioactive components of traditional Chinese medicine, as well as emerging precision technologies such as epigenetic modulation and exosome-based delivery systems, have demonstrated significant anti-fibrotic potential by modulating TXNIP expression and its downstream signaling networks. This review systematically summarizes recent advances in understanding the role of TXNIP in multi-organ fibrosis, with a focus on its core molecular mechanisms and organ-specific functions. It also explores current therapeutic strategies targeting TXNIP and discusses future research directions, summarize current insights that may inform future research into TXNIP-centered anti-fibrotic strategies.