VCAM1 Emerges as the Strongest Molecular Bridge Between Pyrethroids and Keloid Biology
Keloids remain among the most frustrating fibroproliferative skin disorders in clinical practice. They arise from abnormal wound repair, with excessive extracellular matrix deposition and persistent fibrotic remodeling that can keep progressing long after the original injury has healed. In this PLOS ONE study, investigators asked whether pyrethroid insecticides might intersect with the molecular circuitry of keloid formation, and they moved through a long chain of computational and experimental steps to test that possibility.
The central signal pointed to VCAM1. Across the integrated analyses, VCAM1 consistently outperformed the other prioritized candidate and stayed elevated in validation datasets, making it the most coherent molecular link between pyrethroid exposure and keloid-associated changes. FGFR1 also surfaced during prioritization, but its external support was weaker and it did not replicate as robustly in the independent cohort. In practical terms, the study did not identify a broad toxicology signature; it narrowed the field to one gene with repeated support and one weaker companion signal.
Shared Targets, Fibrotic Pathways, and the Biology of Chronic Scarring
The first analytic layer identified 127 shared candidate targets between pyrethroid insecticides and keloid. Those genes clustered mainly in MAPK, PI3K–Akt, and FoxO signaling pathways, all of which fit comfortably within the biology of inflammation, cell survival, and fibrotic remodeling. In a disease such as keloid, sustained signaling through those pathways can favor fibroblast persistence, extracellular matrix accumulation, and the failure of normal scar resolution.
Keloids are not simply thick scars. They reflect a wound-healing program that refuses to shut down, and pathways linked to growth, survival, and immune activation help explain why the process can become self-reinforcing. Pyrethroids, for their part, are widely used insecticides in household and agricultural settings, and prior work has tied them to oxidative stress, immune perturbation, and endocrine disruption. The molecular logic in this paper rests on overlap: if an environmental exposure repeatedly nudges pathways already implicated in fibrotic disease, the biological plausibility for a connection becomes stronger.
Machine Learning Narrowed the Field Without Losing the Signal
From the shared target list, three machine-learning approaches were used to prioritize candidate genes: random forest, support vector machine–recursive feature elimination, and LASSO regression. Only genes retained across all three methods were carried forward as core targets. VCAM1 and FGFR1 emerged from that filtering step, which is a meaningful constraint because the study did not rely on a single algorithmic screen.
The training dataset, GSE145725, showed that both genes had significant differential expression and good discriminatory performance. External validation was more discriminating. In the integrated cohort generated from GSE90051 and GSE158395, VCAM1 remained significantly upregulated and produced an AUC of 0.869, while FGFR1 showed weaker external support, with an AUC of 0.677 and no significant differential expression. Those data separate a durable signal from a candidate that looked useful in discovery but lost strength when tested elsewhere.
VCAM1’s behavior matters because it is biologically tied to endothelial adhesion, leukocyte trafficking, and inflammatory recruitment. In fibrotic skin disease, a gene with that profile can plausibly participate in the maintenance of a pro-inflammatory microenvironment that keeps fibroblasts activated. The result is not a proof of causation, but it is a credible mechanistic bridge between exposure and tissue response.
Experimental Validation Reinforced the Computational Signal
The computational work did not stand alone. Molecular docking and 100-nanosecond molecular dynamics simulation supported the structural plausibility of selected pyrethroid–target interactions, with theta-cypermethrin showing particularly strong support for VCAM1. Those methods do not prove real-world toxicity, but they do indicate that the ligand-target pairing is not chemically implausible.
Single-cell transcriptomic analysis then added cell-type context. It mapped the candidate genes across keloid cellular populations, helping define where the signal may be operating inside the lesion rather than treating the scar as a uniform mass of tissue. Virtual gene perturbation suggested a putative VCAM1–SOCS3 regulatory relationship, opening a second line of hypothesis generation centered on immune regulation and intracellular feedback control.
The laboratory readout was the most direct evidence in the paper. In KEL FIB cells, 20 μM cypermethrin exposure for 24 hours significantly increased VCAM1 mRNA expression by qRT-PCR. One sentence captures the practical consequence: cypermethrin pushed the leading candidate in the same direction seen in the human transcriptomic analyses.
What the Study Can Support, and What Still Needs Proof
The study’s strength lies in its triangulation. Network toxicology, machine learning, external transcriptomic validation, docking, molecular dynamics, single-cell profiling, virtual perturbation, and qRT-PCR all pointed toward VCAM1 as the most consistent candidate linking pyrethroid exposure with keloid-associated molecular alterations. That layered approach reduces the chance that a single noisy dataset drove the result.
The limits are equally clear. The work is largely hypothesis-generating, and the predicted VCAM1–SOCS3 relationship still needs mechanistic validation. The external support for FGFR1 was weaker, and the structural and transcriptomic findings do not establish that environmental pyrethroid exposure causes keloids in patients. Human exposure patterns, dose-response relationships, and tissue-level causality remain unresolved.
Even so, the study offers a more concrete mechanistic framework than a generic association study would. It links a common environmental insecticide class to fibrotic skin biology through a specific adhesion and inflammatory axis, with VCAM1 sitting at the center of the most coherent signal. Future work will need to test whether this relationship survives in vivo and whether it maps onto real-world exposure levels rather than the experimental conditions used here.