Acyl-CoA synthetase short-chain family member 2–Transcription factor EB axis (ACSS2–TFEB axis)

The ACSS2-TFEB axis is a critical metabolic and epigenetic signaling pathway composed of the enzyme Acyl-CoA Synthetase Short Chain Family Member 2 (ACSS2) and the master transcriptional regulator Transcription Factor EB (TFEB) (Li et al., 2017; Nature). ACSS2 facilitates the conversion of acetate into acetyl-CoA, a crucial metabolite that serves as a building block for fatty acids and a donor for histone acetylation in the nucleus (UniProt Q9NR19). In this axis, ACSS2-mediated production of acetyl-CoA promotes the acetylation of histones (such as H3K9) at the promoters of autophagy and lysosomal genes, which directly drives the expression of TFEB (Li et al., 2017). TFEB then orchestrates the Coordinated Lysosomal Expression and Regulation (CLEAR) network to maintain cellular homeostasis and nutrient availability during stress (UniProt P19484). This axis plays a significant role in cancer progression by enabling metabolic flexibility under nutrient-poor conditions and is also implicated in neurodegenerative and lysosomal storage diseases (Xu et al., 2021; Frontiers in Oncology). Therapeutic strategies involve inhibiting ACSS2 to disrupt tumor metabolism or activating TFEB to enhance the autophagic clearance of toxic protein aggregates (Miller et al., 2021; JCI). However, targeting this axis presents challenges regarding systemic metabolic homeostasis and the potential for off-target effects on normal autophagic processes. This entry is classified as "incorrect" in a strict molecular target database because it represents a multi-protein signaling axis rather than a single discrete protein target.

Other names

ACSS2-TFEB pathwayAcetate-ACSS2-TFEB signalingNucleus-localized ACSS2-TFEB axisACSS2-TFEB metabolic regulatory axis

Inhibition of ACSS2 enzymatic activity to deplete nuclear acetyl-CoA pools and reduce TFEB-mediated autophagy; indirect activation of TFEB via mTORC1 inhibition or direct transcriptional modulation.