ACSS2 (Acyl-CoA Synthetase Short Chain Family Member 2)

In comparison, crotonate showed better blocking effect than EZH2 inhibitor tazemetostat in suppressing breast cancer metastasis. The combination of crotonate and anti-PD-L1 (programmed cell death ligand 1) antibody enhances responses of breast cancer cells to immunotherapy. Together, our findings indicate that crotonate is a promising anticancer drug candidate that suppresses breast cancer growth and metastasis by specifically inducing EZH2 degradation.

Although ACSS2 inhibitors have shown therapeutic promise in preclinical studies, only one has progressed to clinical trials, highlighting the need for continued translational research. This review summarizes current insights for obesity-evoked metabolic disorders and cancer progression linked by ACSS2 and suggests future studies on understanding ACSS2 regulatory mechanisms, therapeutic potential, and biomarker utility across obesity-associated diseases.

The identification of GCDH as a potential risk factor in HNC opens new avenues for targeted therapies, offering potential improvements in patient outcomes through precision medicine approaches.

These findings not only illustrate the interplay between metabolic reprogramming, epigenetic modification, and tumorigenesis in the context of HBV infection, but also highlight ACSS2 as a novel metabolic vulnerability in HBV-related HCC. Therefore, targeting ACSS2 could be a novel strategy against HBV-associated HCC.

Our data suggest that USP2, a key molecule mediating the interaction between HCC cells and tumor-associated macrophages, may be a promising therapeutic target for HCC.

ACSS2 is a critical regulator of ovarian cancer growth and invasiveness under hypoxic stress. Targeting ACSS2 may represent a promising therapeutic strategy for managing ovarian cancer. Further studies are warranted to explore its clinical potential.

Consequently, these data provide structural and mechanistic insights into the remarkable selectivity of CoA pocket-targeting Acs inhibitors. As such, targeting fungal and parasitic Acs enzymes for the development of novel anti-infectives can be achieved with high selectivity and, thereby, low host toxicity.

Our findings indicate ACSS2 contributes to endocrine therapy resistance through nuclear acetyl-CoA provision for epigenetic alterations. Targeting these cancer cell adaptations represents a novel therapeutic approach potentially reducing metastasis-related mortality and improving breast cancer treatment outcomes.

Importantly, through pharmacological screening, we identified a histone decrotonylase inhibitor that enhanced EGFR-TKI sensitivity by activating epigenetic reprogramming through the selective upregulation of histone Kcr levels across multiple models in vitro and in vivo. Collectively, our findings uncover a previously unrecognized epigenetic mechanism driven by crotonylation that contributes to EGFR-TKI resistance, highlighting the potential of modulating crotonylation as a novel therapeutic strategy to enhance the efficacy of EGFR-TKIs in lung cancer.

Moreover, the proliferation and invasion status induced by ACSS2 can be partly reversed by BCAT1 in pancreatic cancer cells. In summary, we believe that targeting the ACSS2-PPARD-BCAT1 axis has certain clinical value and can provide a new therapeutic strategy for the comprehensive treatment of pancreatic cancer.

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.