Simultaneous Inhibition of ACLY and OGDH Has a Synergistic Effect in Hepatocellular Carcinoma Cell Lines
Year: 2026
Type: preprint
Abstract: Purpose Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, and current therapies provide limited benefit without offering a definitive cure. This highlights the need for more effective therapeutic strategies. In this study, we investigated whether co-targeting the metabolic enzymes ATP citrate lyase ( ACLY ) and oxoglutarate dehydrogenase ( OGDH ) could induce synthetic lethality in HCC cells. Because valproic acid (VPA) and bempedoic acid (BA), inhibitors of OGDH and ACLY , have not previously been evaluated in combination in HCC, we investigated their potential to induce synthetic lethality in HCC cells. Methods Synthetic lethality was evaluated in HCC cell lines (Hep3B and Huh7) using pharmacological inhibition of OGDH and ACLY with VPA and BA, respectively. The effects of single-agent and combination treatments on cell proliferation were compared, and cytotoxicity was also assessed in the non-cancerous liver cell line THLE-2 to examine selectivity. Drug interaction effects were assessed based on the observed synergistic suppression of HCC cell growth relative to either treatment alone. Results Combined treatment with VPA and BA produced a strong synergistic effect in suppressing proliferation in Hep3B and Huh7 cells compared with either drug alone. In contrast, the combination caused little additional cytotoxicity in THLE-2 cells, suggesting a degree of cancer selectivity. These findings are consistent with previous reports identifying USP13 as a metabolic regulator of ACLY and OGDH in multiple cancers, supporting the idea that the antiproliferative effects of USP13 inhibition in HCC may be mediated through downstream effects on these two enzymes. Conclusions Co-targeting ACLY and OGDH shows promise as a synthetic lethal strategy in HCC and may provide a selective therapeutic approach with limited toxicity in non-cancerous liver cells. These findings support further investigation of ACLY and OGDH as a synthetic lethal pair and of combined VPA-BA treatment as a potential therapeutic strategy for HCC.
Institutions: Shiraz University, Karolinska Institutet, McMaster University
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
Awards: G101103092, G11426272, Proteasome dysfunction as a driver of age-associated risk for Alzheimer's disease onset and progression, G178365870, G343469054, G414656666, G5188874398, G5576255610, G5612768679, G6553588769, G6646225512, G683723002, Precursors of Stroke Incidence and Prognosis, The pathogenic effects of senescent cells on their microenvironments and their role in human brain aging
OpenAlex ID: W7155206645