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Background <p>Drug-induced liver injury (DILI) is a major health concern, often linked to endoplasmic reticulum (ER) stress. Specnuezhenide (SPE), a bioactive iridoid glycoside from <i>Ligustrum lucidum</i>, is known for its hepatoprotective effects, but its role in ER stress–mediated DILI remains unclear. This study investigated the protective mechanisms of SPE against tunicamycin (TM)-induced liver injury, focusing on ER stress and metabolic reprogramming.</p> Methods <p>Male C57BL/6 mice were pretreated with SPE (40, 80, or 160&#xa0;mg/kg) or the positive control 4-phenylbutyric acid (PBA) for seven days, followed by a single intraperitoneal injection of TM (1&#xa0;mg/kg) to induce acute liver injury. Liver injury, lipid profiles, histopathology, ER stress markers, insulin signaling, lipid and cholesterol metabolism, and markers of inflammation and oxidative stress were evaluated.</p> Results <p>SPE pretreatment significantly alleviated TM-induced liver injury, as indicated by reduced serum ALT and AST levels, decreased liver weight, and improved hepatic histopathology. Mechanistically, SPE inhibited activation of the PERK/eIF2α/CHOP axis of the unfolded protein response (UPR), restored metabolic homeostasis by enhancing hepatic insulin sensitivity via the AKT/GSK3β/mTOR pathway, normalized lipid and cholesterol metabolism gene expression, and reduced hepatic steatosis. SPE also attenuated hepatic inflammation and oxidative stress.</p> Conclusions <p>Specnuezhenide protects against TM-induced liver injury through multiple mechanisms, including suppression of ER stress, restoration of metabolic homeostasis, and reduction of inflammation and oxidative stress. Therefore, these findings highlight SPE as a promising therapeutic candidate for DILI.</p>

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Specnuezhenide mitigates tunicamycin-induced liver injury in mice via ER stress modulation and metabolic reprogramming

  • 期刊论文

  • 发表日期：

    2025年8月11日

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  • Tianle Zhang,
  • Dan Bi,
  • Jiahui Li,
  • Xin Jin,
  • Huijuan Wu,
  • Changyuan Yang,
  • Siping Yu,
  • Hedong Rong,
  • Yanhong Yang,
  • Zili Lei

摘要

Background

Drug-induced liver injury (DILI) is a major health concern, often linked to endoplasmic reticulum (ER) stress. Specnuezhenide (SPE), a bioactive iridoid glycoside from Ligustrum lucidum, is known for its hepatoprotective effects, but its role in ER stress–mediated DILI remains unclear. This study investigated the protective mechanisms of SPE against tunicamycin (TM)-induced liver injury, focusing on ER stress and metabolic reprogramming.

Methods

Male C57BL/6 mice were pretreated with SPE (40, 80, or 160 mg/kg) or the positive control 4-phenylbutyric acid (PBA) for seven days, followed by a single intraperitoneal injection of TM (1 mg/kg) to induce acute liver injury. Liver injury, lipid profiles, histopathology, ER stress markers, insulin signaling, lipid and cholesterol metabolism, and markers of inflammation and oxidative stress were evaluated.

Results

SPE pretreatment significantly alleviated TM-induced liver injury, as indicated by reduced serum ALT and AST levels, decreased liver weight, and improved hepatic histopathology. Mechanistically, SPE inhibited activation of the PERK/eIF2α/CHOP axis of the unfolded protein response (UPR), restored metabolic homeostasis by enhancing hepatic insulin sensitivity via the AKT/GSK3β/mTOR pathway, normalized lipid and cholesterol metabolism gene expression, and reduced hepatic steatosis. SPE also attenuated hepatic inflammation and oxidative stress.

Conclusions

Specnuezhenide protects against TM-induced liver injury through multiple mechanisms, including suppression of ER stress, restoration of metabolic homeostasis, and reduction of inflammation and oxidative stress. Therefore, these findings highlight SPE as a promising therapeutic candidate for DILI.