{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T03:07:35Z","timestamp":1789009655752,"version":"build-2803163510"},"posted":{"date-parts":[[2026,4,22]]},"group-title":"Cancer Biology","reference-count":48,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T00:00:00Z","timestamp":1776816000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"NIA","award":["R01AG057896, 1RF1AG063507, R01AG068293, 6 1R01AG0665241A, 1R01AG065301, P30 AG066546, and 1R21AG087907"],"award-info":[{"award-number":["R01AG057896, 1RF1AG063507, R01AG068293, 6 1R01AG0665241A, 1R01AG065301, P30 AG066546, and 1R21AG087907"]}]},{"DOI":"10.13039\/100000065","name":"NINDS","doi-asserted-by":"crossref","award":["RF1NS112391, U19NS115388, and R015R01NS017950-39"],"award-info":[{"award-number":["RF1NS112391, U19NS115388, and R015R01NS017950-39"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Purpose<\/jats:title>\n                  <jats:p>\n                    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 (\n                    <jats:italic>ACLY<\/jats:italic>\n                    ) and oxoglutarate dehydrogenase (\n                    <jats:italic>OGDH<\/jats:italic>\n                    ) could induce synthetic lethality in HCC cells. Because valproic acid (VPA) and bempedoic acid (BA), inhibitors of\n                    <jats:italic>OGDH<\/jats:italic>\n                    and\n                    <jats:italic>ACLY<\/jats:italic>\n                    , have not previously been evaluated in combination in HCC, we investigated their potential to induce synthetic lethality in HCC cells.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    Synthetic lethality was evaluated in HCC cell lines (Hep3B and Huh7) using pharmacological inhibition of\n                    <jats:italic>OGDH<\/jats:italic>\n                    and\n                    <jats:italic>ACLY<\/jats:italic>\n                    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.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    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\n                    <jats:italic>USP13<\/jats:italic>\n                    as a metabolic regulator of\n                    <jats:italic>ACLY<\/jats:italic>\n                    and\n                    <jats:italic>OGDH<\/jats:italic>\n                    in multiple cancers, supporting the idea that the antiproliferative effects of\n                    <jats:italic>USP13<\/jats:italic>\n                    inhibition in HCC may be mediated through downstream effects on these two enzymes.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>\n                    Co-targeting\n                    <jats:italic>ACLY<\/jats:italic>\n                    and\n                    <jats:italic>OGDH<\/jats:italic>\n                    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\n                    <jats:italic>ACLY<\/jats:italic>\n                    and\n                    <jats:italic>OGDH<\/jats:italic>\n                    as a synthetic lethal pair and of combined VPA-BA treatment as a potential therapeutic strategy for HCC.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.04.19.716936","type":"posted-content","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T17:05:14Z","timestamp":1776877514000},"source":"Crossref","is-referenced-by-count":0,"title":["Simultaneous Inhibition of\n                  <i>ACLY<\/i>\n                  and\n                  <i>OGDH<\/i>\n                  Has a Synergistic Effect in Hepatocellular Carcinoma Cell Lines"],"prefix":"10.64898","author":[{"given":"Mehdi Dehghan","family":"Manshadi","sequence":"first","affiliation":[{"name":"Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden"},{"name":"Algorithmic 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