Simultaneous Inhibition of ACLY and OGDH Has a Synergistic Effect on Hepatocellular Carcinoma Cell Lines
Dehghan Manshadi, M.; Setoodeh, P.; Zare, H. · cancer biology · 2026-09-07 · 原文
DOI：10.64898/2026.04.19.716936作者：3 位
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide. Current treatments offer limited efficacy and no definitive cure, underscoring the urgent need for more selective and effective therapeutic strategies. This study investigated the synthetic lethality caused by co-targeting two metabolic genes, ATP citrate lyase (ACLY) and oxoglutarate dehydrogenase (OGDH), in HCC cells. Using valproic acid (VPA) and bempedoic acid (BA) as pharmacological inhibitors of OGDH and ACLY, respectively, we observed a strong synergistic effect in inhibiting the proliferation of HCC cell lines (Hep3B and Huh7), compared to using these drugs individually. Importantly, this combination treatment exhibited little increased cytotoxicity in the non-cancerous liver cell line THLE-2, indicating a degree of selectivity. Our findings are consistent with previous reports implicating USP13 as a metabolic regulator of ACLY and OGDH in various cancers, suggesting that the inhibition of USP13 may prevent HCC cell proliferation primarily through its downstream effects on ACLY and OGDH. By directly co-targeting ACLY and OGDH, our approach may offer a more precise and safer alterna
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1. 人话版
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide.
Current treatments offer limited efficacy and no definitive cure, underscoring the urgent need for more selective and effective therapeutic strategies.
2. 领域脉络
本文类目：cancer biology，属于其所在研究脉络的最新进展。
3. 机制拆解
This study investigated the synthetic lethality caused by co-targeting two metabolic genes, ATP citrate lyase (ACLY) and oxoglutarate dehydrogenase (OGDH), in HCC cells.
4. 证据与数字
Using valproic acid (VPA) and bempedoic acid (BA) as pharmacological inhibitors of OGDH and ACLY, respectively, we observed a strong synergistic effect in inhibiting the proliferation of HCC cell lines (Hep3B and Huh7), compared to using these drugs individually.
Importantly, this combination treatment exhibited little increased cytotoxicity in the non-cancerous liver cell line THLE-2, indicating a degree of selectivity.
Our findings are consistent with previous reports implicating USP13 as a metabolic regulator of ACLY and OGDH in various cancers, suggesting that the inhibition of USP13 may prevent HCC cell proliferation primarily through its downstream effects on ACLY and OGDH.
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