CUMYL-4CN-BINACA exposure is associated with oxidative stress, ER stress-related responses, apoptosis, and altered KIM-1, NGAL, and Nephrin expression in rat kidney.

CUMYL-4CN-BINACA (C-4CN-B), a potent synthetic cannabinoid (SC), is linked to severe systemic toxicity, but its renal molecular toxicity remains unclear. This study examined C-4CN-B-induced nephrotoxicity in male Sprague-Dawley rats, focusing on oxidative stress, inflammation, ER stress, and apoptosis. Thirty-two rats were assigned to four groups and received intraperitoneal C-4CN-B (0.25, 0.5, or 1 mg/kg/day) for 14 days. Serum urea and creatinine increased dose-dependently, indicating impaired renal function. In kidney tissue, MDA levels rose, while GSH content and SOD, CAT, and GPx activities declined, confirming oxidative damage. Gene and protein analyses showed suppression of antioxidant defenses, with decreased Nrf2 and HO-1and increased Keap1 expression. Inflammatory signaling was activated, evidenced by elevated TLR4, IL-6, IL-33, and COX-2. ER stress-related responses were also evident, with increased PERK, and ATF-6 expression, whereas ERK expression suggested activation of downstream stress-associated signaling. Increased KIM-1 and NGAL expression further supported tubular epithelial injury, while altered nephrin expression indicated possible podocyte/glomerular filtration barrier involvement, suggesting that CUMYL-4CN-BINACA-induced renal toxicity may affect both tubular and glomerular compartments and contribute to apoptotic progression. Overall, C-4CN-B caused dose-dependent, multifactorial kidney injury through concurrent activation of oxidative, inflammatory, ER stress, and apoptotic pathways.