Acetyl-CoA synthetase 2 (ACSS2)–Transcription factor EB (TFEB) metabolic axis (ACSS2–TFEB axis)

The Acetyl-CoA synthetase 2–Transcription factor EB (ACSS2–TFEB) metabolic axis is a critical regulatory pathway that links cellular metabolism to epigenetic control and autophagy (Li et al., Nature, 2017; Yin et al., Cell Death & Disease, 2025). Acetyl-CoA synthetase 2 (ACSS2) is an enzyme that converts acetate into acetyl-CoA, and under conditions of metabolic stress or hypoxia, it translocates to the nucleus (Li et al., Nature, 2017; NIH, 2022). In the nucleus, ACSS2 forms a complex with Transcription Factor EB (TFEB), the master regulator of the autophagy-lysosome pathway, and provides a local supply of acetyl-CoA for histone acetylation at the promoters of TFEB target genes (Li et al., Nature, 2017; Yin et al., Cell Death & Disease, 2025). This axis is frequently hijacked by cancer cells, such as those in glioblastoma and breast cancer, to survive in nutrient-poor microenvironments by maintaining autophagic flux (NIH, 2022; Miller et al., 2021). Targeting this axis, primarily through ACSS2 inhibitors like MTB-9655, offers a strategy to disrupt cancer cell energy homeostasis and sensitize tumors to other therapies (ASCO, 2022; NCI, 2022). Beyond oncology, the axis is also implicated in neurodegenerative and metabolic diseases where autophagy and lipid metabolism are dysregulated (NIH, 2025; Yin et al., Cell Death & Disease, 2025). Potential safety concerns include the disruption of basal autophagy in normal tissues and organ-specific metabolic dysregulation, although ACSS2 inhibition has shown a favorable safety profile in early clinical studies (ASCO, 2022; NIH, 2025).

Other names

ACSS2-TFEB signaling pathwayACSS2-TFEB regulatory axisACSS2-TFEB autophagy axisAMPK-ACSS2-TFEB pathway

Inhibition of ACSS2-mediated nuclear acetyl-CoA production, which reduces histone acetylation at TFEB-target gene promoters, thereby suppressing the expression of autophagy and lysosomal genes and inducing metabolic stress in cancer cells.