PHARMACOLOGICAL RESEARCH
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2025
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IF 10.5
Mengdi Zhang,Jinliang Ji,Yuanyuan Lei,Fujian Qin,Yitong Tao,Ning Li,Jinlei Bian,Zhiyu Li,Maode Lai,Zhixia Qiu
Inhibiting de novo lipogenesis (DNL) in hepatocytes is a promising strategy for treating metabolic fatty liver diseases. ACLY, a key enzyme in the DNL pathway, has become a therapeutic target for non-alcoholic fatty liver disease (NAFLD). However, its inhibition shows mixed outcomes, depending on interventions and diets. Evidence suggest ACLY inhibition activates the ACSS2-mediated acetate metabolism and the subsequent DNL, though potential mechanisms and possible consequences remain unclear. This study found that targeting hepatic ACLY with AAV8-shRNA failed to improve NAFLD in mice fed a high-fat, high-fructose diet. Instead, it worsened inflammation and liver injury. ACLY inhibition conditionally upregulated DNL enzymes, but consistently activated the ACSS2-acetyl-CoA pathway and suppressed fatty acid oxidation. Further, ACLY inhibition led to polyunsaturated fatty acid accumulation, triggering mitochondrial dysfunction. The resulting ROS redirected carbon flux into acetate, activating the ACSS2-acetyl-CoA pathway, which promoted lipid biosynthesis and exacerbated mitochondrial dysfunction—a vicious cycle that fueled inflammation and liver damage. Dual inhibition of ACLY and ACSS2 broke this cycle by reducing hepatic acetyl-CoA flux, suppressing DNL, enhancing fatty acid oxidation via PPAR-α activation, and improving mitochondrial function. This combined targeting strategy reduced lipid accumulation, alleviated inflammation, and normalized aminotransferase levels, effectively reversing NAFLD progression.
研究领域:
生物化学
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代谢疾病
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肝脏研究
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DOI
PubMed
高影响因子
ENVIRONMENT INTERNATIONAL
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2024
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IF 10.3
Yunting Li,Anfei Liu,Kaiju Chen,Lifan Li,Xiaoshun Zhang,Fei Zou,Xingmei Zhang,Xiaojing Meng
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.
研究领域:
神经科学
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毒理学
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药理学
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分子生物学
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PubMed
高影响因子
CHEMICAL RESEARCH IN TOXICOLOGY
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2026
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IF 4.1
Wanting Chen,Xian Zhao,Jiaxin Zheng,Zhiru Zheng,Fengxia Qin,Zunjian Zhang,Fengguo Xu,Pei Zhang
Cisplatin (DDP) is a widely used chemotherapeutic agent, but its clinical application is limited by dose-dependent nephrotoxicity. Although metabolic dysregulation is a hallmark of DDP-induced acute kidney injury (AKI), the specific changes in fatty acid oxidation (FAO)-associated metabolic programs and the enzymes linking metabolic disturbances to cell death remain incompletely defined. In this study, targeted metabolomic profiling of the kidney revealed a marked blockade of FAO, evidenced by the accumulation of fatty acids and a decrease in downstream acylcarnitines. Among FAO-related enzymes, acyl-CoA synthetase short-chain family member 2 (ACSS2) emerged as the most significantly downregulated enzyme, which was further confirmed in an ischemia/reperfusion AKI model. ACSS2 overexpression in HK-2 cells aggravated DDP-induced inflammation and apoptosis, whereas ACSS2 knockdown significantly reduced cytotoxicity and pro-inflammatory cytokine production. Furthermore, pharmacological inhibition of ACSS2 in vivo alleviated DDP-induced AKI characterized by reduced oxidative stress and improved renal function. Together, these findings indicate that targeting ACSS2 may represent a promising therapeutic strategy to mitigate DDP-induced renal injury.
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高影响因子
npj Science of Food
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2025
·Vol. 9
·期 1
·234
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IF 7.8
Cao Lixue,Lei Qi,Dong Yujia,Meng Chuyang,Qi Qianqian,Li Lisi,Liu Hongwei,Liu Xifu,Wang Meng
Alcohol abuse results in alcoholic liver disease which are associated with high morbidity and mortality worldwide. Whereas luteolin has shown potential hepatoprotective effects on ethanol-induced liver damage and the underlying mechanism remains unclear. In this study, a chronic plus a single binge ethanol feeding mouse model was employed to mimic acute-on-chronic alcoholic liver injury in humans, and the primary hepatocytes were isolated for the mechanism investigation. Our study demonstrated that luteolin protects against ethanol-induced liver injury by restoring NRF2 stability, thereby blocking the nuclear accumulation of ACSS2 and histone H3 acetylation. This subsequently led to reduced hepatic lipogenesis, and ultimately ameliorated alcoholic liver damage. Our findings elucidate the protective mechanism of luteolin in alcoholic liver injury and provide a new therapeutic strategy for the treatment of alcoholic liver disease.
研究领域:
肝脏病学
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分子生物学
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药理学
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营养生物化学
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PubMed
高影响因子
Nature Communications
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2026
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IF 18.1
Wen Xiao,Wu Keyan,Wang Mengyao,Ma Zihan,Wang Tao,Zhang Jing,Wang Bei,Chen Siyuan,Wang Jingyi,Chen Siyue,Yang Fan,Liu Chuwei,Chen Xianyang,Deng Lu,Cheng Yafan,Miao Qing Robert,Sun Baofa,Ruan Xiongzhong,Li Kai,Duan Yajun,Hu Wenquan
Inflammation is a pivotal driver of the progression from metabolic dysfunction-associated steatotic liver disease (MASLD) to metabolic dysfunction-associated steatohepatitis (MASH), an aggressive form associated with substantial liver-related mortality. However, the molecular mechanisms underlying the initiation and persistence of liver inflammation remain poorly defined. Here, we demonstrated a previously unrecognized role for hepatic acetyl-CoA synthetase short-chain family member 2 (ACSS2) in MASH, showing that ACSS2 upregulation in patients exacerbates MASH progression by functioning as an epigenetic regulator, independent of its canonical lipogenic role. Mechanistically, ACSS2, in complex with lysine acetyltransferase 5 (KAT5), upregulates allograft inflammatory factor-1 ( AIF1 ) transcription via histone crotonylation, thereby inducing liver inflammation and subsequently resulting in the aberrant accumulation of senescent hepatocytes, which further enhances proinflammatory cytokine production. This ultimately initiates a vicious cycle of chronic inflammation, which directly promotes the progression from simple steatosis to MASH. Thus, our work reveals a mechanistically defined and pivotal role for ACSS2 in promoting the MASLD-to-MASH transition, highlighting its potential as a compelling therapeutic target.
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DRUG RESISTANCE UPDATES
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2024
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IF 15.8
Dajun Gao,Yanting Shen,Lingfan Xu,Yi Sun,Hailiang Hu,Bin Xu,Zhong Wang,Huan Xu
Aims Tumor fatty acid (FA) metabolic plasticity plays a pivotal role in resistance to therapy and poses limitations to anticancer strategies. In this study, our aim is to uncover the role of acetate metabolism in neurodifferentiation (NED)-mediated castration-resistant prostate cancer (CRPC). Methods We conducted analyses using LC-MS/MS on clinical prostate cancer tissue before and after hormone therapy. We established tumor xenograft mouse models, primary tumor cells, and human-derived organoids to detect the novel mechanism of NED and to identify potential therapies. Results The hormone therapy-induced upregulation of acetate metabolism was mediated by acyl-CoA synthetase short-chain family member 2 (ACSS2), which increased c-MYC expression for NED induction. Notably, combined treatment with an ACSS2 inhibitor and enzalutamide significantly reduced the xenograft tumor volume. Conclusion Our findings uncovered the critical role of acetate metabolism in NED-mediated CRPC and suggest that ACSS2 inhibitors may represent a novel, low-toxicity strategy when combined with hormone therapy for treating patients with NED-mediated CRPC.
研究领域:
肿瘤学
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分子生物学
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癌症代谢
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前列腺癌
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激素治疗
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PubMed
高影响因子
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