m6A-driven NAT10 translation facilitates fatty acid metabolic rewiring to suppress ferroptosis and promote ovarian tumorigenesis through enhancing ACOT7 mRNA acetylation.

RNA epigenetic modifications have been implicated in cancer progression. However, the interplay between distinct RNA modifications and its role in cancer metabolism remain largely unexplored. Our study demonstrates that N-acetyltransferase 10 (NAT10) is notably upregulated in ovarian cancer (OC), correlating with poor patient prognosis. IGF2BP1 enhances the translation of NAT10 mRNA in an m6A-dependent manner in OC cells. NAT10 drives tumorigenesis by mediating N4-acetylcytidine (ac4C) modification of ACOT7 mRNA, thereby augmenting its stability and translation. This NAT10-ACOT7 axis modulates fatty acid metabolism in cancer cells and promotes tumor progression by suppressing ferroptosis. Additionally, our research identifies fludarabine as a small molecule inhibitor targeting NAT10, inhibits the ac4C modification and expression of ACOT7 mRNA. By using cell derived xenograft model and patient derived organoid model, we show that fludarabine effectively suppresses ovarian tumorigenesis. Overall, our study highlights the pivotal role of the NAT10-ACOT7 axis in the malignant cancer progression, underscoring the potential of targeting NAT10-mediated ac4C modification as a viable therapeutic strategy for this disease.

Lower Serum ATG7 Levels Linked to Insulin Resistance in Women with Polycystic Ovary Syndrome.

BACKGROUND Previous studies have suggested that autophagy, a cellular process regulated by ATG7, plays a critical role in ovarian physiology and pathology. In this study, our objective was to examine ATG7 levels in women with and without polycystic ovary syndrome (PCOS) and to explore potential associations between serum ATG7 levels and PCOS. MATERIAL AND METHODS The study included 188 women diagnosed with PCOS, matched with an equal number of healthy women for comparison. Serum levels of ATG7 were determined using the ELISA technique, and the difference was assessed using an independent samples t test. The association between ATG7 serum levels and the risk of developing PCOS was evaluated by using a multivariable logistic regression model. Additionally, the potential of ATG7 to predict PCOS was investigated through logistic regression and receiver operating characteristic (ROC) analysis. RESULTS Our study found that women with PCOS had significantly lower serum ATG7 levels than their healthy counterparts. Lower ATG7 levels were associated with a higher risk of developing PCOS after adjusting for various confounding variables. The combination of ATG7 with HOMA-IR performed well in predicting PCOS, with an AUC of 92.3%, a sensitivity of 88.3%, and a specificity of 85.3%. CONCLUSIONS Our study found that serum ATG7 levels were significantly lower in women with PCOS and were associated with an increased risk of developing PCOS. This suggests that ATG7 could potentially serve as a biomarker for diagnosing and managing PCOS.

CD36-mediated podocyte lipotoxicity promotes foot process effacement.

Background: Lipid metabolism disorders lead to lipotoxicity. The hyperlipidemia-induced early stage of renal injury mainly manifests as podocyte damage. CD36 mediates fatty acid uptake and the subsequent accumulation of toxic lipid metabolites, resulting in podocyte lipotoxicity. Methods: Male Sprague-Dawley rats were divided into two groups: the normal control group and the high-fat diet group (HFD). Podocytes were cultured and treated with palmitic acid (PA) and sulfo-N-succinimidyl oleate (SSO). Protein expression was measured by immunofluorescence and western blot analysis. Boron-dipyrromethene staining and Oil Red O staining was used to analyze fatty acid accumulation. Results: Podocyte foot process (FP) effacement and marked proteinuria occurred in the HFD group. CD36 protein expression was upregulated in the HFD group and in PA-treated podocytes. PA-treated podocytes showed increased fatty acid accumulation, reactive oxygen species (ROS) production, and actin cytoskeleton rearrangement. However, pretreatment with the CD36 inhibitor SSO decreased lipid accumulation and ROS production and alleviated actin cytoskeleton rearrangement in podocytes. The antioxidant N-acetylcysteine suppressed PA-induced podocyte FP effacement and ROS generation. Conclusions: CD36 participated in fatty acid-induced FP effacement in podocytes via oxidative stress, and CD36 inhibitors may be helpful for early treatment of kidney injury.

NAT10-mediated RNA acetylation enhances HNRNPUL1 mRNA stability to contribute cervical cancer progression.

N4-acetylcytidine (ac4C) is a lately discovered nucleotide modification that has been shown to be closely implicated in cancer. N-acetyltransferase10(NAT10) acts as an enzyme that regulates mRNA acetylation modifications. Currently, the role of NAT10-mediated RNA acetylation modification in cervical cancer remains to be elucidated. On the basis of transcriptome analysis of TCGA and GEO open datasets (GSE52904, GSE29570, GSE122697), NAT10 is upregulated in cervical cancer tissues and correlated with poor prognosis. Knockdown of NAT10 suppressed the cell proliferation, invasion, and migration of cervical cancer cells. The in vivo oncogenic function of NAT10 was also confirmed in xenograft models. Combined RNA-seq and acRIP-seq analysis revealed HNRNPUL1 as the target of NAT10 in cervical cancer. NAT10 positively regulate HNRNPUL1 expression by promoting ac4C modification and stability of HNRNPUL1 mRNA. Furthermore, depletion of HNRNPUL1 suppressed the cell division, invasion, and migration of cervical cancer. HNRNPUL1 overexpression partially restored cellular function in cervical cancer cells with NAT10 knockdown. Thus, this study demonstrates that NAT10 contributes to cervical cancer progression by enhancing HNRNPUL1 mRNA stability via ac4C modification, and NAT10-ac4C-HNRNPUL1 axis might be a potential target for cervical cancer therapy.