Multi-omics uncovers formononetin's protection against antibiotic-induced liver injury via microbiota-metabolite-transcriptome coordination

Tetracycline antibiotics (TETs) cause hepatotoxicity via gut-liver axis disruption and oxidative stress. This study evaluated whether formononetin (FMN), a natural isoflavone, alleviates TET-induced liver injury through microbiota-metabolite-transcriptome coordination. Using network toxicology and pharmacology, we predicted key targets and pathways involved. A mouse model of TET-induced injury (150 mg/kg, 3 days) was treated with FMN (50 or 100 mg/kg) for 14 days. Multi-omics analyses revealed that FMN attenuated hepatic steatosis, reduced ALT/AST levels, enhanced gut microbial diversity (enriched Limosilactobacillus), and restored intestinal barrier integrity. Mechanistically, FMN activated the Nrf2/HO-1 antioxidant pathway, modulated PPARα/CYP2E1-dependent lipid metabolism, and inhibited ferroptosis. FMN demonstrates multi-target hepatoprotection by coordinating microbiota restoration, oxidative stress reduction, and metabolic reprogramming, supporting its potential as a dietary intervention against antibiotic-related liver damage.

四环素类抗生素（Tetracycline Antibiotics, TETs）可通过破坏肠-肝轴与诱发氧化应激引发肝毒性。本研究旨在评估天然异黄酮类化合物芒柄花素（Formononetin, FMN）是否可通过调控菌群-代谢物-转录组的协同作用，缓解四环素类抗生素诱导的肝损伤。本研究借助网络毒理学与药理学方法，预测了相关核心靶点与通路。研究构建了四环素类抗生素诱导的小鼠肝损伤模型（给药剂量150 mg/kg，造模时长3天），随后以50或100 mg/kg的芒柄花素对模型小鼠进行为期14天的干预治疗。多组学分析结果显示，芒柄花素可减轻小鼠肝脂肪变性，降低血清谷丙转氨酶（ALT）与谷草转氨酶（AST）水平，提升肠道微生物多样性（富集莱姆乳酸杆菌属Limosilactobacillus），并修复肠道屏障完整性。从机制层面来看，芒柄花素可激活核因子E2相关因子2/血红素氧合酶1（Nrf2/HO-1）抗氧化通路，调控过氧化物酶体增殖物激活受体α/细胞色素P450 2E1（PPARα/CYP2E1）依赖的脂质代谢过程，并抑制铁死亡（ferroptosis）。芒柄花素可通过协同修复肠道菌群、减轻氧化应激与重塑代谢模式，实现多靶点肝脏保护作用，这表明其有望成为对抗抗生素相关性肝损伤的膳食干预手段。