Cell Death & Disease
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2021
·Vol. 12
·期 12
·1-13
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IF 8.469
Tan Yanjie,Jin Yi,Zhao Pengxiang,Wu Jian,Ren Zhuqing
Lipid droplet (LD), a multi-functional organelle, is found in most eukaryotic cells. LDs participate in the regulation of many cellular processes including proliferation, stress, and apoptosis. Previous studies showed the athlete’s paradox that trained athletes accumulate LDs in their skeletal muscle. However, the impact of LDs on skeletal muscle and myogenesis is not clear. We discovered that C2C12 myoblast cells containing more LDs formed more multinucleated muscle fibers. We also discovered that LDs promoted cell migration and fusion by promoting actin-filaments remodeling. Mechanistically, two LD-proteins, Acyl-CoA synthetase long chain family member 3 (ACSL3) and lysophosphatidylcholine acyltransferase 1 (LPCAT1), medicated the recruitment of actinin proteins which contributed to actin-filaments formation on the surface of LDs. During remodeling, the actinin proteins on LDs surface translocated to actin-filaments via ARF1/COPI vesicles. Our study demonstrate LDs contribute to cell differentiation, which lead to new insight into the LD function.
研究领域:
细胞生物学
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分子生物学
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肌肉生理学
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PubMed
高影响因子
Advanced Science
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2026
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IF 14.1
Liang Xu,Wanying Xiang,Xinyue Wang,Yue Pan,Jing Gao,Jiezhen Yang,Yufei Wang,Zhipu Zhu,Man Tong,Lei Jin,Yan Ye
Platinum-based chemotherapy resistance remains a major obstacle in gastric cancer (GC) treatment. Through integrated transcriptomic profiling of cisplatin-resistant xenografts and pharmacogenomic interrogation of the NCI-60 dataset, we identified Prohibitin-2 (PHB2) as a previously unrecognized determinant of chemoresistance. PHB2 was consistently upregulated in resistant tumors and associated with poor clinical outcomes. Mechanistically, PHB2 binds the lipid-metabolic enzyme ACSL3 through a defined AMP-binding–domain interface (residues W244/H254/E260), enhancing ACSL3 activity to promote monounsaturated fatty acid incorporation into phospholipids. This phospholipid remodeling suppresses lipid peroxidation and establishes a ferroptosis-resistant state. Structure-based virtual screening of an FDA-approved drug library nominated the CXCR4 antagonist Mavorixafor as a potent inhibitor of the PHB2–ACSL3 interaction. Mavorixafor disrupted lipid remodeling, restored ferroptosis susceptibility, and resensitized cisplatin-resistant GC in cell line–derived xenografts (CDOs) and patient-derived organoids (PDOs). The therapeutic effect was abrogated by the ferroptosis inhibitor Liproxstatin-1, confirming ferroptosis dependence. Collectively, our findings define a PHB2–ACSL3 lipid-metabolic axis that drives ferroptosis escape and identify Mavorixafor repurposing as an immediately translatable strategy to overcome cisplatin resistance in treatment-refractory GC.
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高影响因子
EXPERIMENTAL NEUROLOGY
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2026
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IF 4.8
Zhenyu Wu,Xufang Huo,Yubing Huang,Taowu Gong,Pengcheng Zhao,Yuhang Zhu,Qingfan Zeng
Although hypertension (HYP) consistently predicts cognitive decline, the precise pathogenic cascade within the brain remains elusive. Here we interrogated whether the PPARγ/ACSL3 axis governs HYP-elicited hippocampal ferroptosis and consequent cognitive dysfunction. This study aimed to explore the role of the PPARγ/ACSL3 axis in HYP-induced neuronal ferroptosis and cognitive impairment. In the HYP rat model, behavioral tests (Morris water maze and Y-maze tests) demonstrated that rats in the hypertensive group had a significant decline in learning and memory. Mechanistically, the AngII-AT1R axis was found to be activated in the hippocampus, accompanied by typical ultrastructural features of ferroptosis, increased iron accumulation, elevated oxidative stress, and downregulation of PPARγ, ACSL3, and key ferroptosis defense proteins (GPX4, XCT, and FPN1). In vitro, ACSL3 overexpression alleviated AngII-induced neuronal ferroptosis. Furthermore, the PPARγ agonist rosiglitazone attenuated lipid peroxidation and iron overload by transcriptionally upregulating ACSL3, a direct regulatory relationship confirmed by dual-luciferase reporter assay. In conclusion, under hypertensive conditions, BRAS activation inhibits the PPARγ/ACSL3 axis via the AngII-AT1R pathway, aggravates lipid peroxidation and ferroptosis in hippocampal neurons, and ultimately contributes to cognitive decline. This study provides new experimental evidence for the mechanism research and therapeutic target exploration of HYP-related cognitive impairment.
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高影响因子
PHYTOMEDICINE
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2025
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IF 8.3
Xiaoyu Tao,Yifei Gao,Zhengsen Jin,Shan Lu,Zhiqi Li,Siyu Guo,Qiqi Fan,Jiaqi Li,Chuanqi Qiao,Huiling Lei,Zhiqiang Zhang,Chongjun Zhao,Jiarui Wu
Background The combined therapeutic mechanisms of evodiamine (EVO) and berberine (BBR), which are the primary bioactive components contributing to the pharmacological effects of Euodiae Fructus and Rhizoma Coptidis , a classic herb pair used for colitis, have not yet been fully elucidated Purpose This study aimed to investigate the critical mechanisms by which co-administration EVO and BBR mitigated EVO-induced hepatotoxicity while exerting therapeutic effects against colitis. Methods Safety and therapeutic outcomes of EVO alone and combined BBR were validated in normal and colitis models. RNA-seq sequencing was performed on liver and colon tissues from different groups, while metagenomic sequencing was utilized to analysis fecal samples. An integrated bioinformatics analysis of transcriptomic and metagenomic data was conducted to reveal the mechanisms underlying EVO-induced hepatotoxicity and the protective and synergistic effects of BBR against colitis. Molecular biology experiments were employed to validate the regulatory mechanism, with a particular emphasis on the interactions within the gut- liver axis, including those related to lipid metabolism and inflammatory pathways. Results BBR attenuated EVO-induced hepatotoxicity in C57 mice by ameliorating pathological injuries and hepatic steatosis as well as inhibiting abnormal AST/ALT elevation, thereby revealing its hepatoprotective effects. In colitis mice, the combination therapy exhibited enhanced efficacy in reducing mucosal damage, restoring goblet cells populations, and suppressing pro-inflammatory cytokines production compared to monotherapy. Integrated analysis of RNA-seq combined with experimental validation revealed that EVO-induced hepatotoxicity was associated with the disrupted fatty acid β-oxidation and cholesterol synthesis homeostasis. Notably, co-administration of BBR effectively rescued metabolic disturbance through modulating core regulatory targets such as ACSL1, CPT1B, SQLE, DHCR7. Additionally, the combination treatment synergistically inhibited IL-17/NF-κB signaling, upregulated tight junction proteins, and rectified gut microbiota dysbiosis, thereby alleviating intestinal injury in colitis mice. Furthermore, ACSL3, a central regulator of fatty acid β-oxidation, was identified as a pivotal target through which the combination of EVO combined BBR suppressed lipid peroxidation-mediated activation of IL-17/NF-κB, leading to alleviate inflammation in LPS-induced NCM460 cell. Conclusion ACSL3 was identified as the critical therapeutic target through underlying the amelioration of fatty acid metabolism-mediated inflammatory injury in colitis by the combined administration of EVO and BBR, thereby offering a scientific foundation for precise and safe clinical drug administration.
研究领域:
药理学
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毒理学
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胃肠病学
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系统生物学
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生物信息学
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分子生物学
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民族药理学
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代谢
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免疫学
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PubMed
高影响因子
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