Sorafenib,a multi-kinase inhibitor for advanced hepatocellular carcinoma(HCC),often encounters resistance within months of treatment,limiting its long-term efficacy.Despite extensive efforts,reliable plasma biomarkers...Sorafenib,a multi-kinase inhibitor for advanced hepatocellular carcinoma(HCC),often encounters resistance within months of treatment,limiting its long-term efficacy.Despite extensive efforts,reliable plasma biomarkers to monitor drug activity remain elusive.Here,we demonstrate that metabolic reprogramming is a strategic response implemented by cancer cells to survive the therapeutic pressure.Sorafenib suppresses oxidative phosphorylation by disrupting electron transport chain supercomplex assembly and enhancing glycolysis.To mitigate the accumulation of harmful glycolytic byproducts such as advanced glycation endproducts(AGEs),sorafenib-treated cells reroute excess dihydroxyacetone phosphate(DHAP)toward glycerol-3-phosphate(G3P)synthesis,supporting glycerolipid metabolism,NAD^(+)regeneration,and redox balance,rather than producing D-lactate via the glyoxalase pathway.Alongside,resistant cells enhance serine metabolism to boost glutathione synthesis,reinforcing antioxidant defenses.Additionally,sorafenib increases reliance on exogenous non-esterified free fatty acids and triglycerides for phospholipid remodeling.The combined effects of glycerolipid remodeling and enhanced antioxidant capacity facilitate ferroptosis escape,diminishing sorafenib’s activity.Leveraging these metabolic insights,we validate our findings by investigating plasma metabolites alteration in HCC patients.We identify D-lactate accumulation as a predictor of treatment response and glycerol accumulation as a marker of resistance,highlighting their potential as novel biomarkers for sorafenib activity.As sorafenib is used in advanced HCC,early detection of treatment response is critical to guiding the therapeutic decision,optimizing treatment strategies,and improving patient outcomes.展开更多
基金supported by the Ministry of University and Research(MUR)Progetto Eccellenza(2023-2027)to the Department of Pharmacological and Biomolecular Sciences“Rodolfo Paoletti,”Universita degli Studi di Milano,and partially by the Italian Ministry of Health with Ricerca Corrente and“5xmille”funds to N.Msupported by Fondazione Umberto Veronesi post-doctoral fellowship+5 种基金supported by a European Commission Horizon Europe Marie Skłodowska-Curie Actions Doctoral Networks(MSCA-DN)ETERNITY project(grant agreement number:101072759)coordinated by N.Msupported by Progetti di Rilevante Interesse Nazionale(PRIN 20227KTSAT to GDN)PNRR Missione 4(Progetto CN3-National Center for Gene Therapy and Drugs based on RNA Technology to GDN)PNRR Missione 4(Progetto MUSA-Multilayered Urban Sustainability Action to GDN)PNRR Missione 6(PNRR-MAD-2022-12375913 to GDN)CARDINNOV,Ministry of Research and University under the umbrella of the Partnership Fostering a European Research Area for Health(ERA4Health)(grant agreement number:101095426 of the EU Horizon Europe Research and Innovation Programme to GDN),European Atherosclerosis Society(EAS)Research grant 2023 to LDD.
文摘Sorafenib,a multi-kinase inhibitor for advanced hepatocellular carcinoma(HCC),often encounters resistance within months of treatment,limiting its long-term efficacy.Despite extensive efforts,reliable plasma biomarkers to monitor drug activity remain elusive.Here,we demonstrate that metabolic reprogramming is a strategic response implemented by cancer cells to survive the therapeutic pressure.Sorafenib suppresses oxidative phosphorylation by disrupting electron transport chain supercomplex assembly and enhancing glycolysis.To mitigate the accumulation of harmful glycolytic byproducts such as advanced glycation endproducts(AGEs),sorafenib-treated cells reroute excess dihydroxyacetone phosphate(DHAP)toward glycerol-3-phosphate(G3P)synthesis,supporting glycerolipid metabolism,NAD^(+)regeneration,and redox balance,rather than producing D-lactate via the glyoxalase pathway.Alongside,resistant cells enhance serine metabolism to boost glutathione synthesis,reinforcing antioxidant defenses.Additionally,sorafenib increases reliance on exogenous non-esterified free fatty acids and triglycerides for phospholipid remodeling.The combined effects of glycerolipid remodeling and enhanced antioxidant capacity facilitate ferroptosis escape,diminishing sorafenib’s activity.Leveraging these metabolic insights,we validate our findings by investigating plasma metabolites alteration in HCC patients.We identify D-lactate accumulation as a predictor of treatment response and glycerol accumulation as a marker of resistance,highlighting their potential as novel biomarkers for sorafenib activity.As sorafenib is used in advanced HCC,early detection of treatment response is critical to guiding the therapeutic decision,optimizing treatment strategies,and improving patient outcomes.
