ACSS2-TFEB axis acts as a critical regulator of the autophagic machinery in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) has a high rate of metastasis and recurrence, and poses a considerable threat to patient survival. Autophagy, an intracellular degradation pathway, plays a crucial role in tumor progression; however, the underlying mechanisms of action remain unclear. This study aimed to explore the role of the ACSS2-TFEB axis in the regulation of autophagy and its impact on HNSCC cell proliferation, migration, invasion, and lysosomal function. HNSCC tumor tissues and cell lines were analyzed for ACSS2 protein expression. The effects of the ACSS2 knockdown on cell proliferation, migration, invasion, and autophagic flux were also assessed. The interaction between ACSS2 and transcription factor EB (TFEB) and its influence on lysosomal function were also examined. In this study, we found that ACSS2 protein expression was significantly upregulated and correlated with metastasis and poor prognosis. ACSS2 knockdown inhibited the proliferation, migration, and invasion of HNSCC cells, and disrupted autophagy flux, primarily by impairing lysosomal function. Additionally, ACSS2 was found to sustain autophagic flux through TFEB activation, a key regulator of the autophagy-lysosome pathway. TFEB activation promotes lysosomal function and autophagic flux, thereby facilitating tumor cell growth and metastasis. This study elucidated the molecular mechanism by which ACSS2 enhances HNSCC cell proliferation and invasion via TFEB activation. The ACSS2-TFEB axis is a potential therapeutic target for HNSCC and provides a foundation for the development of targeted therapies.