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Insulin Resistance and Cutaneous Squamous Cell Carcinoma: A Narrative Review of Molecular Mechanisms

Articles InPress

Document Type : Review Article

Authors

1 Department of Physiology, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia

2 Department of Anatomic Pathology, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia

3 Department of Dermatology and Venereology, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia

4 Department of Internal Medicine, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia

10.30476/ijms.2025.106644.4091

Abstract

Although the association between diabetes and cutaneous squamous cell carcinoma (cSCC) is well recognized, the specific role of insulin resistance (IR) as an independent driver of cSCC pathogenesis remains underexplored. This review synthesized emerging evidence on the ultraviolet (UV)-independent molecular mechanisms by which IR promotes cSCC initiation and progression. Hyperinsulinemia activates the insulin-like growth factor-1 receptor (IGF-1R), which triggers both the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathways, stimulating keratinocyte proliferation and suppressing apoptosis. In parallel, hyperglycemia-driven formation of advanced glycation end products (AGEs) and oxidative stress cause deoxyribonucleic acid (DNA) damage and impair tumor suppressor functions, notably that of tumor protein p53 (TP53). The resulting reactive oxygen species (ROS) activate nuclear factor-kappa B (NF-κB), establishing a chronic inflammatory milieu that remodels the tumor microenvironment through cytokines, including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), and by upregulating matrix metalloproteinases (MMPs). These processes collectively facilitate the malignant transformation of actinic keratosis (AK) to invasive cSCC. The analysis in the present study identified novel therapeutic targets and reaffirmed the importance of further studies on microbiome interactions and lifestyle interventions for IR-associated cSCC.

Highlights

Dedi Ardinata (Google Scholar)
Tengku Ibnu Alferraly (Google Scholar)

Keywords

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Iranian Journal of Medical Sciences

Articles InPress, Corrected Proof
Available Online from 07 July 2026
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  • Received: 12 April 2025
  • Revised: 10 August 2025
  • Accepted: 06 October 2025
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