The synthetic cannabinoid CUMYL-4CN-BINACA induces hepatic injury in rats via oxidative stress, NF-κB activation, Nrf2 suppression, EDEM-1, ER stress-mediated apoptotic pathways

DOĞAN T., AKSAKAL Ö., ALAT Ö., HALICI M. B., GÜR C.

FOOD AND CHEMICAL TOXICOLOGY, cilt.207, 2026 (SCI-Expanded, Scopus) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 207
  • Basım Tarihi: 2026
  • Doi Numarası: 10.1016/j.fct.2025.115809
  • Dergi Adı: FOOD AND CHEMICAL TOXICOLOGY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, PASCAL, Aqualine, Aquatic Science & Fisheries Abstracts (ASFA), BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, Chemical Abstracts Core, Chimica, EMBASE, Environment Index, Food Science & Technology Abstracts, Pollution Abstracts, Veterinary Science Database
  • Atatürk Üniversitesi Adresli: Evet

Özet

Synthetic cannabinoids (SCs), particularly CUMYL-4CN-BINACA (C-4CN-B), are highly potent psychoactive substances linked to systemic toxicity, including liver injury. This study evaluated the dose-dependent hepatotoxic effects of C-4CN-B and the underlying molecular pathways in male Sprague Dawley rats. Thirty-two animals were divided into four groups (n = 8): a control group receiving vehicle (2 % ethanol, 2 % Tween 80, 96 % saline) and three treatment groups administered C-4CN-B intraperitoneally at 0.25, 0.5, or 1.0 mg/kg for 14 days. Liver function markers (ALT, AST, ALP) were analyzed biochemically. Oxidative stress indicators, including malondialdehyde (MDA) and reduced glutathione (GSH), were measured, while antioxidant enzymes (SOD, CAT, GPx) and apoptosis/inflammation-related proteins (Bax, Bcl-2, Caspase-3, NF-kappa B, TNF-alpha, IL-1 beta) were assessed via ELISA. Western blotting detected Keap-1, TLR-4, NF-kappa B, TNF-alpha, IL-6, IL-1 beta, HO-1, and Nrf2 expression. RT-qPCR profiled genes regulating oxidative and ER stress, including XBP-1, CHOP, GRP78, ATF4, EDEM1, Nrf2, and HO1. C-4CN-B exposure caused dose-related increases in liver enzymes and MDA, alongside depletion of GSH and antioxidant enzymes. Pro-inflammatory cytokines and apoptotic markers were markedly upregulated. Molecular analyses showed NF-kappa B/TLR-4 activation, suppression of Nrf2/HO-1, and induction of ER stress genes. These findings indicate that C-4CN-B induces hepatotoxicity through oxidative stress, ER stress, and inflammatoryapoptotic signaling.