Furthermore, significant associations are found among low nuclear ACAT1 levels, decreased S60 phosphorylation, and reduced NK cell infiltration, as well as poor prognosis in CRC. Our findings reveal an unexpected function of ACAT1 as a nuclear acetyltransferase and elucidate its role in NK cell-dependent antitumor immunity through p50 acetylation.

Targeting ACAT1 to inhibit ME2 acetylation effectively reduced chemoresistance in both in vitro and in vivo models. These findings underscore the significance of acetylated ME2-mediated lactate production from glutamine in chemoresistance, particularly under conditions of reduced intracellular glucose within cancer cell, thereby complementing the Warburg effect and offering new perspectives on the metabolic links to chemotherapy resistance.

This research contributed to the growing body of evidence supporting the role of metabolic modulators in cancer therapy and emphasized the importance of understanding tumor microenvironments to optimize treatment outcomes. However, the need for further research into the metabolic pathways is underscored to enhance therapeutic strategies for cancer treatment.

Here, we demonstrated that Sirtuin 5 (SIRT5), a member of the deacetylase SIRT family, functions as a desuccinylase of acetyl-CoA acetyltransferase 1 (ACAT1) and enhances the enzymatic activity of ACAT1 to activate the NRF2 pathway, inhibiting the secretion of the chemokines CCL5 and CXCL10, which are important for recruiting CD8+ T cells, thereby participating in the formation of an inhibitory TIME in EGFR-mutant LUAD. In conclusion, we propose that the combination of a SIRT5 inhibitor with ICIs therapy may be a promising therapeutic approach for patients with EGFR-mutant LUAD.

Importantly, ACAT1 negatively regulated the choline metabolic pathway, which is crucial for the differentiation of GBM cells. Finally, we demonstrated that a naturally available substance, chlorogenic acid (CHA), could inhibit phosphorylation of ACAT1 and so delay GBM progression, CHA is a promising candidate to treat GBM because it could induce the differentiation of cancer cells.

The results demonstrate that F26 is more effective and durable than F12511 in inhibiting ACAT1, in both mouse embryonic fibroblasts (MEFs), and in multiple mouse tissues including the brain tissues, without exhibiting any overt systemic or neurotoxic effects. This study demonstrates the superior pharmacokinetic and safety profile of F26 in wild-type mice, and suggests its therapeutic potential against various neurodegenerative diseases including AD.

In addition, ACAT1 overexpression inhibited cell migration and invasion, improved the response to 5-Fluorouracil (5-FU) and etoposide. Correlation analysis indicated ACAT1 mRNA expression was correlated with immune infiltrates. Collectively, our data show that ACAT1 induces pronounced inhibitory effects on gastric cancer initiation and development, which may impact future strategies to treat this aggressive cancer.

SPXJ formula inhibited proliferation, invasion, and migration of HCC cells by decreasing plasma membrane cholesterol levels and altering cellular stiffness through upregulation of ACAT1 protein expression.

Collectively, our findings underscore ACAT1 as a pivotal tumor suppressor, instrumental in curtailing the proliferation, migration, and invasion of ccRCC by governing fatty acid metabolism through the AMPK signaling pathway. These insights posit ACAT1 as a potential predictive biomarker and therapeutic target warranting further exploration in RCC management.

Mechanistic assays revealed that ACAT1 enhances BLCA cell proliferation and metastasis through the AKT/GSK3β/c-Myc signaling pathway by modulating the cell cycle and EMT. Taken together, the results of our study reveal that ACAT1 is an oncogenic driver in BLCA that enhances tumor proliferation and metastasis, indicating its potential as a diagnostic and therapeutic target for this disease.

ACAT1 inhibition may be exploited as a potential strategy to enhance the anti-tumor immunity and eliminate tumors. Herein, a comprehensive understanding of the role of ACAT1 in tumor development and anti-tumor immunity may provide new insights for anti-tumor strategies.

Moreover, the knockdown of ACAT1 led to better anti-tumor efficacy of anti-CD19 CAR-T cells in the B-cell lymphoma mice model. Our study demonstrates novel CAR-T cells containing ACAT1 shRNA with improved efficacy compared to conventional anti-CD19-CAR-T cells in vitro and in vivo.