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Mangiferin targeting HSP90α induces DNA damage in cutaneous squamous cell carcinoma via the ROS/MAPK signaling

Liyun Jie1, He Huang2, LuYing Sha3

  • 1School of Clinical Medicine, Guizhou Medical University, No.9 Beijing Road, Yunyan District, Guiyang 550004, Guizhou, China; Department of Dermatology and Venereology，The Second People's Hospital of Bijie City, Middle Section of Caohai Avenue, Qixingguan District, Bijie 551700, Guizhou,China.

International Immunopharmacology
|November 22, 2025
PubMed

Insights

Mangiferin (MF) effectively treats cutaneous squamous cell carcinoma (cSCC) by targeting HSP90α and activating the ROS/MAPK pathway. This natural compound inhibits tumor growth and promotes apoptosis with minimal toxicity.

Area of Science:

  • Oncology
  • Dermatology
  • Pharmacology

Background:

  • Cutaneous squamous cell carcinoma (cSCC) presents a significant clinical challenge due to high recurrence and drug resistance.
  • Novel therapeutic strategies and drug targets are crucial for improving cSCC treatment outcomes.
  • Mangiferin (MF) has demonstrated anti-tumor properties, including inhibition of proliferation, apoptosis induction, and regulation of oxidative stress in various cancers.

Purpose of the Study:

  • To investigate the therapeutic potential and underlying mechanisms of Mangiferin (MF) in cutaneous squamous cell carcinoma (cSCC).
  • To identify the molecular targets and pathways through which MF exerts its anti-cSCC effects.

Main Methods:

  • In vitro assays (CCK-8, EDU) to assess MF's effects on A431 cSCC cells.
  • Network pharmacology, molecular docking, and molecular dynamics simulations to predict MF targets.
  • CETSA and DARTS experiments to validate MF-HSP90α interaction.
  • Genetic manipulation (knockdown/overexpression) of HSP90α.
  • ROS generation and MAPK pathway analysis.
  • In vivo studies in a cSCC mouse model.

Main Results:

  • MF significantly inhibited A431 cell proliferation, induced apoptosis, and caused G0/G1 cell cycle arrest.
  • HSP90α was identified as a direct target of MF, highly expressed in cSCC tissues.
  • MF-induced apoptosis and DNA damage were mediated by ROS generation and subsequent MAPK pathway activation.
  • MF suppressed cSCC tumor growth in vivo without observable organ toxicity.
  • HSP90α knockdown enhanced apoptosis, while overexpression reduced MF efficacy.

Conclusions:

  • Mangiferin (MF) demonstrates potent anti-cSCC activity both in vitro and in vivo.
  • MF primarily targets HSP90α, leading to ROS generation, mitochondrial/DNA damage, and MAPK pathway activation, ultimately inhibiting cSCC progression.
  • MF represents a promising therapeutic agent for cSCC with a favorable safety profile.
Keywords:
Cutaneous squamous cell carcinomaDNA damageHSP90αMAPKMangiferinROS

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