biostudies-literatureFilliol ANIDDK NIH HHSMedical Research CouncilNCI NIH HHSWellcome TrustNIH HHS356-365https://www.ebi.ac.uk/biostudies/studies/S-EPMC9949942biostudies-literatureUnknown610(7931)Hepatocellular carcinoma (HCC), the fourth leading cause of cancer mortality worldwide, develops almost exclusively in patients with chronic liver disease and advanced fibrosis^1,2. Here we interrogated functions of hepatic stellate cells (HSCs), the main source of liver fibroblasts³, during hepatocarcinogenesis. Genetic depletion, activation or inhibition of HSCs in mouse models of HCC revealed their overall tumour-promoting role. HSCs were enriched in the preneoplastic environment, where they closely interacted with hepatocytes and modulated hepatocarcinogenesis by regulating hepatocyte proliferation and death. Analyses of mouse and human HSC subpopulations by single-cell RNA sequencing together with genetic ablation of subpopulation-enriched mediators revealed dual NatureOpposing roles of hepatic stellate cell subpopulations in hepatocarcinogenesis.PMC9949942219542/Z/19/ZR01 DK116620U01 CA274295F31 DK091980R01 CA233794P30 DK132710R01 CA234128R01 CA211794P30 CA013696S10 OD020056R37 CA258829R01 DK128955R01 CA228483R01 CA262424R01 CA190844R21 CA263381Dobie RSavage TMCaviglia JMSaito YDapito DHWallace SRavichandra ACaruso SSu HFriedman RAArpaia NIzar BSun QWang XRodriguez-Fiallos OMFilliol AAmin ADBhattacharjee SHoshida YKang JKHenderson NCChin LZucman-Rossi JYu LXChen DPajvani UBWilson-Kanamori JRSchwabe RFTabas IYin DFujiwara NYin CRemotti HEAffo SMehal AWells RGNair AKarin MfalseOpposing roles of hepatic stellate cell subpopulations in hepatocarcinogenesis.Hepatocellular carcinoma (HCC), the fourth leading cause of cancer mortality worldwide, develops almost exclusively in patients with chronic liver disease and advanced fibrosis^1,2. Here we interrogated functions of hepatic stellate cells (HSCs), the main source of liver fibroblasts³, during hepatocarcinogenesis. Genetic depletion, activation or inhibition of HSCs in mouse models of HCC revealed their overall tumour-promoting role. HSCs were enriched in the preneoplastic environment, where they closely interacted with hepatocytes and modulated hepatocarcinogenesis by regulating hepatocyte proliferation and death. Analyses of mouse and human HSC subpopulations by single-cell RNA sequencing together with genetic ablation of subpopulation-enriched mediators revealed dual 2022-01-01T00:00:00Z2022 Oct2026-05-28T22:52:22.083Z2025-02-19T04:20:45.746ZS-EPMC99499423619880210.1038/s41586-022-05289-6