Dual targeting of ACSS2 and ACLY by a novel inhibitor S8588 suppresses oncogenic lipogenesis and overcomes metabolic compensation in oral squamous cell carcinoma

Metabolic reprogramming, particularly enhanced lipid anabolism, is a hallmark of oral squamous cell carcinoma (OSCC), yet effective therapies targeting this process remain lacking. Here, we identify concurrent activation of acetyl-CoA synthetase 2 (ACSS2) and ATP-citrate lyase (ACLY) as a cooperative metabolic driver of OSCC progression. Whereas previous efforts have focused on single-enzyme inhibition, we show that ACSS2 and ACLY form a compensatory network that sustains lipid anabolism and drives OSCC progression, providing a rationale for their dual inhibition. Integrative transcriptomic and lipidomic analyses reveal a metabolically aggressive OSCC subset defined by concurrent ACSS2 and ACLY upregulation, which was associated with poor clinical outcomes. Dual inhibition of ACSS2 and ACLY depleted acetyl-CoA, suppressed lipogenesis, and impaired tumor growth in vitro and in vivo. We further identified S8588, a quinoxaline-based small molecule, as a dual-target degrader that induces ubiquitin-proteasome-dependent degradation of both ACSS2 and ACLY, thereby blocking OSCC proliferation. Mechanistically, S8588 directly binds key residues of both enzymes, promoting their proteasomal turnover. Supplementation with acetate and citrate reverses its anti-tumor effect, confirming acetyl-CoA depletion as the primary mechanism. Collectively, our findings establish ACSS2/ACLY co-activation as a therapeutic vulnerability in OSCC and nominate S8588 as a promising dual-target therapeutic to dismantle metabolic adaptability for improved treatment.