Introduction

Cutaneous squamous cell carcinoma (cSCC) represents a significant health burden globally, particularly for individuals with extensive ultraviolet ray exposure. This malignant skin cancer arises from epidermal keratinocytes and exhibits varying degrees of aggressiveness. Recent research has shed light on the role of PLOD2 in cSCC progression, identifying it as a critical mediator of tumor growth and metastasis. Understanding these molecular drivers is essential for developing targeted therapies that can improve patient outcomes in clinical practice.

The Role of the STAT3/PLOD2/ERK-AKT Axis

Researchers have discovered that Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) is frequently upregulated in human cSCC tissues. This enzyme is vital for stabilizing collagen intermolecular cross-links, which supports the structural integrity of the tumor microenvironment. Consequently, the study revealed that PLOD2 acts as a downstream effector of the STAT3 signaling pathway. This activation subsequently triggers the ERK and AKT pathways, which are well-known drivers of cell proliferation, migration, and survival. Therefore, the STAT3/PLOD2/ERK-AKT axis serves as a primary engine for malignancy in cSCC cells.

Minoxidil as a Potential Therapeutic Agent

One of the most promising findings involves the potential repurposing of minoxidil. Although traditionally used for hypertension and alopecia, minoxidil appears to function as a potent inhibitor of PLOD2 in cSCC progression. In experimental models, topical application of minoxidil suppressed tumor development and reduced collagen deposition. Because minoxidil is already clinically approved, it offers a faster pathway toward clinical implementation as a specialized treatment for cSCC. This discovery provides a novel therapeutic strategy for dermatologists and oncologists managing advanced skin cancers.

Clinical Significance for Dermatologists

For clinicians in India, where sun exposure is often high, these findings offer a deeper understanding of cSCC pathophysiology. In addition to surgical excision, targeting the collagen-modifying enzymes could provide an adjunctive method to prevent recurrence. Furthermore, the identification of a safe, repurposed drug like minoxidil simplifies the transition from laboratory research to bedside care. However, further clinical trials are necessary to standardize the dosage and application methods for oncology patients.

Frequently Asked Questions

How does PLOD2 contribute to skin cancer?

PLOD2 facilitates the formation and stability of collagen cross-links. This process modifies the extracellular matrix, creating a scaffold that promotes the migration, invasion, and angiogenesis of cancer cells.

Can minoxidil be used to treat skin cancer today?

While experimental models show that minoxidil inhibits PLOD2 and suppresses tumor growth, it is currently not an approved standard treatment for cSCC. Clinicians should wait for human clinical trial results before using it off-label for this purpose.

What is the STAT3/PLOD2/ERK-AKT axis?

It is a signaling pathway where STAT3 activates PLOD2, which then triggers the ERK and AKT pathways. This chain of events drives the aggressive biological behaviors of cutaneous squamous cell carcinoma.

Disclaimer: This content is for informational and educational purposes only. It does not constitute medical advice or a substitute for professional consultation. Refer to the latest local and national guidelines for clinical practice.

References

Xian N et al. PLOD2 Promotes Cutaneous Squamous Cell Carcinoma Progression in Association With STAT3-Related ERK and AKT Pathways. Mol Carcinog. 2026 Mar 01. doi: 10.1002/mc.70102. PMID: 41764770.

Gjaltema RAF, et al. Roles of PLODs in Collagen Synthesis and Cancer Progression. Front Genet. 2018;9:168. doi: 10.3389/fgene.2018.00168.