Title : Modulation of the ACLY–AMPK axis by bempedoic acid suppresses NF-?B-driven inflammation, VEGF–notch angiogenic crosstalk, and cell-cycle progression in solid ehrlich carcinoma

Aim: This study examined whether Bempedoic Acid (BPA) suppresses SEC progression through an integrated pharmacological framework with toxicological relevance, targeting metabolic, inflammatory, oxidative, angiogenic, proliferative, and apoptotic pathways.

Methods: Fifty female Swiss albino mice were assigned to five groups (n = 10): normal control, untreated SEC control, SEC + Bempedoic Acid (10 or 30 mg/kg, orally), and SEC + doxorubicin (5 mg/kg, i.p.) three times weekly for two weeks as a reference chemotherapeutic comparator with established clinical toxicity relevance. After experiment completion, blood and tumor tissues were obtained for molecular assessment.

Results: SEC-bearing mice showed lipid dysregulation, with elevated ACLY, ACC, FASN, total cholesterol, and triglycerides, alongside suppressed AMPK. BPA counteracted these changes by inhibiting ACLY-driven lipogenesis and restoring AMPK-related signaling, thereby reducing NF-κB pathway activity and iNOS, IL-6, and TNF-α. It also attenuated oxidative stress, increasing SOD and lowering p-carbonyls. Moreover, BPA reduced VEGF, MMP-2, MMP-9, Hes-1, DLL4, Notch-1, and Jagged-1, indicating impaired angiogenic remodeling and endothelial differentiation. Decreased Cyclin-D1 and PCNA reflected reduced proliferation, while increased p53, Bax, and Caspase-3 indicated enhanced apoptosis. Histologically, BPA promoted dose-dependent tumor necrosis, reduced viable anaplastic cell clusters, and induced fibrovascular granulation tissue with peripheral inflammatory cell infiltration, indicating tumor regression and reparative remodeling.

Conclusion: These findings provide preclinical evidence that BPA reduces SEC tumor burden by modulating the ACLY/AMPK-related metabolic pathway, accompanied by suppression of inflammatory, angiogenic, proliferative, survival, oxidative stress, and apoptosis-related dysregulation, supporting its repurposing potential as a multi-target therapeutic candidate for solid tumors.

Keywords: Bempedoic Acid, ACLY, AMPK, Solid Ehrlich Carcinoma, Mechanistic Toxicology.

To be updated shortly..