Improving Sorafenib Efficacy in HCC Tumour Cores via PDE5 Inhibitor‐Mediated Vasodilation in Hypoxic Microenvironments: Targeting the Glycolytic Pathway

Sorafenib is a first-line treatment for hepatocellular carcinoma (HCC) that inhibits tumour cell proliferation but faces challenges such as modest response rates, side effects, and drug resistance. Ongoing research seeks better treatments and combinations to improve outcomes, which are hindered by drug resistance, inadequate tumour tissue accumulation, and poor penetration. Phosphodiesterase type 5 (PDE5) inhibitors, typically used for erectile dysfunction and pulmonary hypertension, show anticancer potential by relaxing smooth muscle and enhancing blood flow. This study investigates the combination of PDE5 inhibitors, like sildenafil and tadalafil, with sorafenib in an alcohol-aflatoxin B1-induced HCC model. The results indicate that this combination enhances the efficacy of sorafenib, increases HCC cell sensitivity, and may help overcome resistance through an ERK-independent mechanism. The combination therapy not only improves treatment effectiveness but also restores normal cellular functions disrupted by aflatoxin B1 exposure, such as metabolic pathways, glycolysis reduction, and p53 function restoration. Overall, this approach holds promise for overcoming sorafenib resistance in HCC by improving drug accumulation and tumour cell penetration.