Berberine increases the sensitivity of sorafenib in human hepatocellular carcinoma via inducing HIF-1α-mediated energy crisis.

Background

Hepatocellular carcinoma (HCC) often develops resistance to sorafenib (SORA), a multikinase inhibitor that has long been a cornerstone of systemic therapy for advanced HCC, leading to cancer progression and poor survival. Strategies to enhance the therapeutic efficacy of SORA in HCC are therefore urgently needed.

Purpose

This study aimed to investigate whether berberine (BBR), a natural isoquinoline alkaloid, could act as a metabolic modulator to overcome SORA resistance in HCC and to elucidate the underlying metabolic mechanisms.

Methods

In vitro and in vivo models, transcriptomic and metabolomic analyses, genetic rescue experiments, and clinical tissue microarray analysis were employed to evaluate the sensitizing effect of BBR in SORA-resistant HCC.

Results

BBR enhanced the antitumor efficacy of SORA to suppress HCC cell proliferation, induce apoptosis, and reduce orthotopic tumor growth in mice. Transcriptomic and metabolomic analyses revealed that BBR disrupted energy homeostasis by concurrently inhibiting glycolysis and oxidative phosphorylation. Mechanistically, BBR suppressed hypoxia-inducible factor 1α (HIF-1α), thereby downregulating the key glucose-metabolizing enzymes phosphofructokinase platelet type (PFKP) and lactate dehydrogenase A (LDHA) in HCC cells. Restoration of PFKP and LDHA expression or stabilization of HIF-1α reversed the metabolic and antitumor effects of BBR and SORA cotreatment. Clinically, HIF-1α, PFKP, and LDHA were overexpressed in HCC tissues and correlated with molecular features previously linked to SORA resistance.

Conclusion

These findings provide functional evidence that BBR sensitizes HCC to SORA by inducing an HIF-1α/PFKP/LDHA-mediated energy crisis, highlighting the preclinical potential of BBR as a candidate adjuvant agent for overcoming SORA resistance in HCC.