mtdsRNA‑driven endoplasmic reticulum stress contributes to trichloroethylene‑induced immune kidney injury

Exposure to trichloroethylene (TCE) can cause occupational medicamentose-like dermatitis and severe immune-related kidney damage. Existing treatments focusing on TNF-α and complement pathways show limited effectiveness against TCE-induced kidney injury, with unclear molecular mechanisms. This study explores the involvement of mitochondrial double-stranded RNA (mt-dsRNA) in TCE-related kidney damage and its regulatory pathways. Patients with occupational medicamentose-like dermatitis due to TCE (OMDT) showed higher serum lipopolysaccharide (LPS) levels, especially in severe cases. Both in vivo and in vitro studies indicated that LPS reduced PNPT1 expression, leading to mt-dsRNA release, triggering the PKR/eIF2α/ATF4/CHOP pathway, causing endoplasmic reticulum (ER) stress and apoptosis. By boosting PNPT1 or inhibiting mitochondrial RNA polymerase with inhibitor of mitochondrial transcription 1(IMT1) decreased mt-dsRNA production and reduced cell damage. These findings suggest that TCE exposure increases systemic LPS, which suppresses PNPT1, causing pathological mt-dsRNA buildup. This activates PKR-dependent ER stress, leading to tubular injury.