Lead is an environmentally widespread neurotoxic pollutant. Although the neurotoxicity of lead has been found to be closely associated with metabolic disorders, the effects of short-chain fatty acids on the neurotoxicity of lead and its mechanisms have not yet been explored. In this study, the results of open field tests and Morris water maze tests demonstrated that chronic lead exposure caused learning and memory deficits and anxiety-like symptoms in mice. The serum butyric acid content of lead-treated mice decreased in a dose-dependent manner, and oral administration of butyrate significantly improved cognitive memory impairment and anxiety symptoms in lead-exposed mice. Moreover, butyrate alleviated neuroinflammation caused by lead exposure by inhibiting the STAT3 signaling in microglia. Butyrate also promoted the expression of acetyl-CoA synthetase ACSS2 in hippocampal neurons, thereby increasing the content of acetyl-CoA and restoring the expression of both histone H3K9ac and the downstream BDNF. We also found that the median butyric acid concentration in high-lead exposure humans was remarkably lower than that in the low-lead exposure humans (45.16 μg/L vs. 60.92 μg/L, P < 0.01), and that butyric acid significantly mediated the relationship of lead exposure with the Montreal cognitive assessment scores, with a contribution rate of 27.57 %. In conclusion, our results suggest that butyrate supplementation is a possible therapeutic strategy for lead-induced neurotoxicity.
Tong Sha,Kun Jiao,Jianing Li,Ye Zheng,Linbin Wang,Zhi Cui
Oral squamous cell carcinoma (OSCC) is an aggressive head and neck malignancy. Lysine acetyltransferase 2B (KAT2B) exerts tumor-suppressive functions in various cancers, yet its function in OSCC remains unclear. Through integrative analysis of five public transcriptomic datasets with validation in clinical tissues and cell lines, we identified a consistent reduction of KAT2B expression in OSCC. Functional assays demonstrated that KAT2B overexpression inhibited OSCC cell proliferation, tumorsphere formation, stemness marker expression, and in vivo tumor growth, whereas KAT2B silencing produced opposite effects. Furthermore, KAT2B overexpression enhanced RSL-3-induced ferroptosis, evidenced by increased Fe 2+ accumulation, elevated lipid reactive oxygen species (ROS) levels, aggravated mitochondrial damage, and reduced GPX4 protein; conversely, KAT2B knockdown conferred ferroptosis resistance. Mechanistically, integrating mRNA sequencing with the FerrDb database identified glutathione S-transferase zeta 1 (GSTZ1) (log 2 FC = 1.44, p < 0.001) as a key downstream target of KAT2B in ferroptosis regulation. ChIP-qPCR confirmed that KAT2B transcriptionally activates GSTZ1 by enhancing histone H3 lysine 9 acetylation (H3K9ac) enrichment at its promoter. Rescue assays further confirmed that depletion of GSTZ1 counteracted the effects of KAT2B overexpression on OSCC cell proliferation and ferroptosis. Collectively, we find that KAT2B transcriptionally activates GSTZ1 in a H3K9ac-dependent manner, which in turn inhibits GPX4 expression, thereby suppressing OSCC proliferation and stemness while enhancing ferroptosis sensitivity. This defines the KAT2B-GSTZ1 axis as a novel tumor-suppressive mechanism and an emerging therapeutic target for OSCC
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