The Combined Inhibition of SREBP and mTORC1 Signaling Synergistically Inhibits B‐Cell Lymphoma

Abstract

ABSTRACT Background The sterol regulatory element‐binding protein (SREBP) pathway is essential for maintaining sterol homeostasis during B cell activation and germinal center B cell proliferation. However, its potential as a therapeutic target to treat B‐cell lymphoma remains unclear. Methods We examined SREBP protein expression in human B‐cell lymphoma samples using immunohistochemistry. Additionally, we conducted in vitro studies using SREBP signaling inhibitors in combination with rapamycin to assess their effects on cell proliferation and lipid metabolism in B‐cell lymphoma cells. Results Our analysis revealed high levels of SREBP2 protein expression in human B‐cell lymphoma samples. Inhibiting SREBP signaling or its downstream target HMG‐CoA reductase (HMGCR) with Fatostatin or Simvastatin effectively suppressed B‐cell lymphoma cell proliferation. However, B‐cell lymphoma cells responded to statin treatment by activating the mTORC1‐pS6 pathway, suggesting a compensatory mechanism to overcome statin‐induced cell cycle arrest. Combining low‐dose statin treatment with the mTOR inhibitor rapamycin produced a synergistic effect, significantly inhibiting B‐cell lymphoma proliferation, cell cycle progression, and lipid raft formation. Conclusions These results highlight the potential of a combined therapeutic approach targeting both SREBP and mTORC1 as a novel strategy for treating B‐cell lymphoma.