Liver cancer, consisting mainly of
hepatocellular carcinoma, is the third leading cause of
cancer-related mortality worldwide. Despite advances in targeted
therapies, these approaches remain insufficient in meeting the pressing clinical demands. Here, we present a novel alternative that calls for a non-apoptotic program to solve the current dilemma. Specifically, we identified that tubeimoside 2 (TBM-2) could induce methuosis in
hepatocellular carcinoma cells, a recently recognized mode of cell death characterized by pronounced vacuolization,
necrosis-like membrane disruption, and no response to
caspase inhibitors. Further proteomic analysis revealed that TBM-2-driven methuosis is facilitated by the hyperactivation of the MKK4-p38α axis and the boosted lipid metabolism, especially
cholesterol biosynthesis. Pharmacological interventions targeting either the MKK4-p38α axis or
cholesterol biosynthesis effectively suppress TBM-2-induced methuosis, highlighting the pivotal role of these mechanisms in TBM-2-mediated cell death. Moreover, TBM-2 treatment effectively suppressed
tumor growth by inducing methuosis in a xenograft mouse model of
hepatocellular carcinoma. Taken together, our findings provide compelling evidence of TBM-2's remarkable
tumor-killing effects by inducing methuosis, both in vitro and in vivo. TBM-2 represents a promising avenue for the development of innovative and effective
therapies for
hepatocellular carcinoma, one that may ultimately offer significant clinical benefits for patients with this devastating disease.