Promoting effect of cadmium on the progression of metabolic dysfunction-associated steatohepatitis and the interventional efficacy of melatonin

QIAN Chuan; LIU Qiu-hong; CAI Jing-shu; LIU Cong; XU Shang-cheng

doi:10.11659/jjssx.02E026079

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Promoting effect of cadmium on the progression of metabolic dysfunction-associated steatohepatitis and the interventional efficacy of melatonin

Basic Research | 更新时间：2026-07-24

- Promoting effect of cadmium on the progression of metabolic dysfunction-associated steatohepatitis and the interventional efficacy of melatonin
- JOURNAL OF REGIONAL ANATOMY AND OPERATIVE SURGERY Vol. 35, Issue 7, Pages: 584-592(2026)
- 作者机构：
  
  1.南京医科大学公共卫生学院，江苏南京 211166
  2.突发中毒应急检测和紧急救治重庆市卫生健康委重点实验室/重庆市职业病防治院，重庆 400060
- 作者简介：
- 基金信息：
- DOI：10.11659/jjssx.02E026079
  CLC： R124
- Received：14 February 2026，
  
  Revised：2026-04-29，
  
  Accepted：18 May 2026，
  
  Online First：24 July 2026，
  
  Published：25 July 2026
- 稿件说明：
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钱川,刘秋宏,蔡静姝等.镉在代谢功能障碍相关脂肪性肝炎进展中的促进作用及褪黑素的干预效应[J].局解手术学杂志,2026,35(07):584-592.

QIAN Chuan,LIU Qiu-hong,CAI Jing-shu,et al.Promoting effect of cadmium on the progression of metabolic dysfunction-associated steatohepatitis and the interventional efficacy of melatonin[J].JOURNAL OF REGIONAL ANATOMY AND OPERATIVE SURGERY,2026,35(07):584-592.
钱川,刘秋宏,蔡静姝等.镉在代谢功能障碍相关脂肪性肝炎进展中的促进作用及褪黑素的干预效应[J].局解手术学杂志,2026,35(07):584-592. DOI： 10.11659/jjssx.02E026079.

QIAN Chuan,LIU Qiu-hong,CAI Jing-shu,et al.Promoting effect of cadmium on the progression of metabolic dysfunction-associated steatohepatitis and the interventional efficacy of melatonin[J].JOURNAL OF REGIONAL ANATOMY AND OPERATIVE SURGERY,2026,35(07):584-592. DOI： 10.11659/jjssx.02E026079.

摘要

目的

探讨镉（Cd）促进代谢功能障碍相关脂肪性肝炎（MASH）进展中的关键靶点与相关通路，并分析褪黑素（MLT）在其进展中的拮抗作用及潜在机制。

方法

采用网络毒理学分析筛选Cd促进MASH进展的信号通路及核心靶点，然后用分子对接方法评估MLT与候选靶点的亲和力。实验验证方面，先在Cd暴露联合胆碱缺乏的L-氨基酸限定高脂饮食诱导的MASH小鼠模型上，采用HE、Masson、Sirius Red染色及F4/80免疫组化染色评估小鼠肝脂肪变性、纤维化及炎性浸润程度；然后，在Cd暴露联合棕榈酸钠（PA）诱导脂毒性的人肝癌细胞系HepG2细胞模型上检测活性氧（ROS）、丙二醛（MDA）含量与超氧化物歧化酶（SOD）活性评价氧化应激水平，采用脂滴绿色荧光（BODIPY）染色检测脂质蓄积程度。在上述研究基础上联合MLT干预，探讨MLT在Cd促进MASH进展中的作用及潜在机制。

结果

网络毒理学分析提示，Cd促进MASH进展可能与FOXO、PI3K-AKT、TNF等炎症和氧化应激通路相关，其候选靶点为TNF、IL-6、TP53、AKT1等。分子对接结果显示

，MLT与TNF、IL-6、TP53、AKT1、RELA、TLR4等核心靶点具有较好的亲和力。体内实验表明，Cd暴露加重肝组织损伤、纤维化、脂肪变性及炎性浸润程度；体外实验显示，Cd暴露可增强PA诱导的脂毒性，表现为ROS水平和MDA含量升高，SOD活性下降，脂质蓄积增加（

0.05）；MLT干预后，上述病理学改变、氧化应激损伤及脂质蓄积均得到改善（

0.05）。

结论

Cd暴露可促进MASH进展，可能与FOXO、PI3K-AKT、TNF等通路及TNF、IL-6、TP53、AKT1等靶点有关；MLT与上述靶点具有较好的亲和力，可通过干扰炎症及氧化应激通路减轻Cd在MASH进展中的促进作用。

Abstract

Objective

To explore the key targets and relevant pathways of cadmium （Cd）‑promoted metabolic dysfunction-associated steatohepatitis （MASH） progression， and to analyze the antagonistic effect and underlying mechanism of melatonin （MLT） against this progression.

Methods

Network toxicology analysis was adopted to screen signaling pathways and core targets of Cd‑promoted MASH progression， and molecular docking was then performed to assess the binding affinity between MLT and the candidate targets. For experimental verification， a MASH mouse model induced by Cd exposure combined with choline-deficient L-amino acid-defined high-fat diet was established. HE staining， Masson staining， Sirius Red staining and F4/80 immunohistochemical staining were used to evaluate the degrees of hepatic steatosis， fibrosis and inflammatory infiltration in mice. Furthermore， a human hepatoma cell line HepG2 model of lipotoxicity was constructed via Cd exposure combined with sodium palmitate （PA） treatment. Oxidative stress levels were determined by detecting reactive oxygen species （ROS）， malondialdehyde （MDA） content and superoxide dismutase （SOD） activity， and lipid accumulation was detected by green fluorescence （BODIPY） staining. Based on the above experiments， MLT intervention was further conducted to investigate the role and underlying mechanism of MLT in Cd‑promoted MASH progression.

Results

Network toxicology analysis indicated that Cd‑promoted MASH progression might be related to inflammatory and oxidative

stress pathways including FOXO， PI3K-AKT and TNF， and candidate targets such as TNF， IL-6， TP53 and AKT1. Molecular docking results revealed that MLT exhibited good binding affinity to core targets including TNF， IL-6， TP53， AKT1， RELA and TLR4. In vivo experiments demonstrated that Cd exposure aggravated liver tissue injury， fibrosis， steatosis and inflammatory infiltration. In vitro experiments showed that Cd exposure exacerbated PA-induced lipotoxicity， manifested as elevated ROS level and MDA content， reduced SOD activity and increased lipid accumulation （

0.05）. After MLT intervention， the above pathological changes， oxidative stress damage and lipid accumulation were all significantly improved （

0.05）.

Conclusion

Cd exposure accelerates the progression of MASH， possibly involving FOXO， PI3K-AKT， TNF pathways and targets including TNF， IL-6， TP53 and AKT1. MLT exhibits favorable binding affinity to the above targets and attenuates the promoting effect of Cd on MASH progression by modulating inflammatory and oxidative stress pathways.

关键词

Keywords

references

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