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Background <p>People living with HIV (PLWH) frequently experience non-AIDS comorbidities, driven in part by persistent intestinal barrier dysfunction and systemic inflammation. The HIV-1 envelope protein gp120 has been implicated in damaging epithelial tight junctions. However, therapeutic options for preserving intestinal integrity are limited.</p> Methods <p>A Caco-2 cell monolayer model was used to simulate HIV-1 gp120–induced intestinal barrier injury. Barrier integrity, tight junction protein expression, apoptosis, and MAPK/ERK1/2 pathway activity were evaluated in the presence or absence of Quercetin. Transcriptomic analysis and Western blotting were performed to investigate mechanisms, including the role of dual-specificity phosphatases (DUSPs) and myosin light chain kinase (MLCK).</p> Results <p>Gp120 exposure increased epithelial permeability, decreased tight junction protein expression (ZO-1, Occludin, Claudin-1), and induced apoptosis. Quercetin treatment significantly restored barrier integrity, reduced apoptosis, and enhanced tight junction expression. Mechanistically, Quercetin suppressed ERK1/2 phosphorylation, upregulated DUSP4, DUSP5, and DUSP8, and inhibited downstream MLCK/MLC activation. The MEK inhibitor U0126 produced similar protective effects, confirming ERK1/2 involvement.</p> Conclusions <p>Quercetin alleviates gp120-induced intestinal barrier disruption via inhibition of the ERK1/2-MLCK signaling pathway and restoration of tight junction proteins. These findings highlight the therapeutic potential of Quercetin as a natural compound to protect against HIV-related mucosal injury and support its further development for managing HIV-associated comorbidities.</p>

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Quercetin ameliorates HIV-1 gp120 protein-induced intestinal barrier dysfunction by inhibiting the activation of the ERK1/2 signaling pathway in a Caco-2 cell model

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月6日

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  • Lijiao Zhu,
  • Jiangyu Yan,
  • Qinghui Wang,
  • Xiaoqing He,
  • Xiaolei Xu,
  • Jiadan Yang,
  • Jing Ouyang

摘要

Background

People living with HIV (PLWH) frequently experience non-AIDS comorbidities, driven in part by persistent intestinal barrier dysfunction and systemic inflammation. The HIV-1 envelope protein gp120 has been implicated in damaging epithelial tight junctions. However, therapeutic options for preserving intestinal integrity are limited.

Methods

A Caco-2 cell monolayer model was used to simulate HIV-1 gp120–induced intestinal barrier injury. Barrier integrity, tight junction protein expression, apoptosis, and MAPK/ERK1/2 pathway activity were evaluated in the presence or absence of Quercetin. Transcriptomic analysis and Western blotting were performed to investigate mechanisms, including the role of dual-specificity phosphatases (DUSPs) and myosin light chain kinase (MLCK).

Results

Gp120 exposure increased epithelial permeability, decreased tight junction protein expression (ZO-1, Occludin, Claudin-1), and induced apoptosis. Quercetin treatment significantly restored barrier integrity, reduced apoptosis, and enhanced tight junction expression. Mechanistically, Quercetin suppressed ERK1/2 phosphorylation, upregulated DUSP4, DUSP5, and DUSP8, and inhibited downstream MLCK/MLC activation. The MEK inhibitor U0126 produced similar protective effects, confirming ERK1/2 involvement.

Conclusions

Quercetin alleviates gp120-induced intestinal barrier disruption via inhibition of the ERK1/2-MLCK signaling pathway and restoration of tight junction proteins. These findings highlight the therapeutic potential of Quercetin as a natural compound to protect against HIV-related mucosal injury and support its further development for managing HIV-associated comorbidities.