Beyond Redox Regulation: Novel Roles of TXNIP in the Pathogenesis and Therapeutic Targeting of Kidney Disease

Am J Pathol. 2025 Apr;195(4):615-625. doi: 10.1016/j.ajpath.2024.12.011. Epub 2025 Jan 13.

Abstract

Cellular stress, such as oxidative and endoplasmic reticulum (ER) stresses, contributes to the development of various kidney diseases. Oxidative stress is prompted by reactive oxygen species accumulation and delicately mitigated by glutathione and thioredoxin (Trx) antioxidant systems. Initially identified as a Trx-binding partner, Trx-interacting protein (TXNIP) is significantly up-regulated and activated by oxidative and ER stresses. The function of TXNIP is closely linked to its subcellular localizations. Under normal physiological conditions, TXNIP primarily localizes to the nucleus. When exposed to reactive oxygen species or ER stress, TXNIP relocates to mitochondria and binds to mitochondrial Trx2, which releases Trx-tethered apoptosis signal-regulating kinase 1 and activates apoptosis signal-regulating kinase 1-mediated apoptosis. Oxidative and ER stresses are also closely associated with autophagy. TXNIP can promote or inhibit autophagy depending on context. Although recent studies have highlighted the indispensable role of TXNIP in the etiology and progression of kidney disease, TXNIP-targeted therapy is still missing. This review focuses on the following: i) oxidative and ER stresses; ii) regulation and function of TXNIP during cellular stress; iii) TXNIP in stress-regulated autophagy; iv) TXNIP in kidney diseases (nephrotic syndrome, diabetic nephropathy and chronic kidney disease, acute kidney injury, and kidney aging); and v) novel treatment agents targeting TXNIP in kidney disease. Current advances in chemical compounds and RNA-based therapy suppressing TXNIP are also reviewed.

Publication types

  • Review

MeSH terms

  • Animals
  • Carrier Proteins* / metabolism
  • Endoplasmic Reticulum Stress / physiology
  • Humans
  • Kidney Diseases* / drug therapy
  • Kidney Diseases* / metabolism
  • Kidney Diseases* / pathology
  • Kidney Diseases* / therapy
  • Oxidation-Reduction
  • Oxidative Stress / physiology
  • Reactive Oxygen Species / metabolism
  • Thioredoxins / metabolism

Substances

  • Carrier Proteins
  • TXNIP protein, human
  • Thioredoxins
  • Reactive Oxygen Species