Disrupting TERT-USP7 interaction to induces telomere-dependent senescence in hepatocellular carcinoma via mannose metabolism modulation

Abstract Induction of cellular senescence is an emerging therapeutic strategy for hepatocellular carcinoma (HCC) that exhibits inherent limited responsiveness to targeted therapies. However, the existing therapeutic methodologies for senescence induction predominantly depend on nonspecific stressors with largely unclarified molecular mechanisms. Herein, we first identify that HCC is characterized by compromised mannose metabolism, and exogenous mannose supplementation or enhancement to promote mannose metabolism can specifically induce telomere-dependent senescence in HCC cells. Mechanistically, mannose metabolism promotes USP7 glycosylation for disrupting the interaction between TERT and USP7 and enhancing K48-linked ubiquitination of TERT, which ultimately triggers telomere-dependent senescence. Notably, senescent HCC cells became more sensitive to senolytic therapy, and further combination of mannose with senolytics markedly enhances antitumor efficacy both in vitro and in vivo. Collectively, this study reveals a metabolic vulnerability linking mannose metabolism to telomere-dependent senescence in HCC and provides a theoretical basis for combining mannose with senolytic agents as a promising therapeutic strategy for HCC.