β‐Caryophyllene Mitigates Thioacetamide‐Induced Liver Fibrosis Through CB2‐Mediated Suppression of Necroptosis: A Therapeutic Investigation

Abstract

ABSTRACT β‐Caryophyllene (BCP), a selective agonist of cannabinoid receptor type 2 (CB2), has garnered attention as a promising nutraceutical agent for modulating organ damage. The current study aimed at evaluating the pharmacological role of BCP in Thioacetamide (TAA)‐induced liver fibrosis, with particular attention to the involvement of CB2‐mediated signaling. Following the induction of fibrosis by TAA, rats were treated with BCP for 6 weeks. In a separate group, AM630, a selective CB2 receptor antagonist, was co‐administered with BCP in order to validate CB2‐dependent actions. TAA administration triggered significant hepatocellular injury. In addition, TAA activated necroptotic cellular death, shown in the upregulated RIPK1/RIPK3/p‐MLKL expression. Growth factors' signaling was disrupted and liver regeneration was impaired. On the contrary, BCP treatment ameliorated oxidative stress, mitigated inflammation, and decreased hepatic stellate cells' activation. This was accompanied by reduced collagen deposition and attenuated fibrosis. BCP markedly abrogated necroptosis and decreased the stimulation of fibrogenic and angiogenic signaling. Additionally, BCP potentiated hepatocytes' survival and restored hepatic regenerative capacity. AM630 co‐treatment abolished BCP's protective effects, confirming the CB2 receptors‐dependent effects. Given findings highlight BCP as a potential therapeutic agent for liver fibrosis and delineate endocannabinoid system's role in modulating organ fibrosis.