Protective potential of bempedoic acid as an AMPK activator in tamoxifen-induced steatohepatitis in rats.

Despite the beneficial therapeutic effects of tamoxifen (TAMX) against breast cancer, long-term treatment with TAMX enhances the development of metabolic dysfunction-associated steatotic liver disease (MASLD), including steatohepatitis. Bempedoic acid (BA) is a recently approved lipid-lowering drug for dyslipidemia. Our study aimed to examine the potential impact of BA against TAMX-induced steatohepatitis in rats and underline the possible molecular pathways involved. Twenty-four adult female rats were allocated into 4 groups (n = 6): Control, TAMX (45 mg/kg), BA (15 mg/kg), and BA (30 mg/kg) groups. BA was given orally by gavage for 15 consecutive days. TAMX was administered to all rats except the normal control rats. Co-treatment of BA with TAMX showed well-organized structures of the hepatocytes in the histopathological sections. BA significantly improved liver function and lipid profile, demonstrating dose-dependent hepatoprotective effects. Mechanistically, BA significantly decreased oxidative stress by decreasing the level of malondialdehyde (MDA) and increasing the level of superoxide dismutase (SOD), significantly reduced inflammatory cytokines such as nuclear factor-kappa B (NF-κB/p65) and tumor necrosis factor-alpha (TNF-α), significantly inhibited lipogenesis by decreasing sterol regulatory element binding protein 1c (SREBP-1c), fatty acid synthetase (FAS), acetyl-coenzyme A carboxylases (ACC), ATP-citrate lyase (ACL), and significantly promoted fatty acid oxidation be enhancing carnitine palmitoyl transferase 1 significantly (CPT-1) through AMP-activated protein kinase (AMPK) activation. These findings suggest BA as a potential adjunct therapy for TAMX-induced metabolic dysfunction-associated steatohepatitis (MASH).