Fibroblasts Identified as Key Drivers of Inflammation in Hidradenitis Suppurativa, New Study Shows

Researchers from Johns Hopkins University have uncovered new evidence suggesting that fibroblasts—not just keratinocytes—play a central role in fueling hidradenitis suppurativa (HS) inflammation.

HS is a chronic, painful dermatologic condition characterized by nodules, abscesses, sinus tracts, and scarring that can severely affect quality of life. Although HS affects up to 1% of the population, its underlying biological mechanisms have remained difficult to define, preventing the development of more targeted therapies. This new research, though, opens the door to potential new treatment strategies.¹⁻³

Fibroblasts Emerge as Active Players in HS Inflammation

Historically, HS research has focused on the role of keratinocytes, the predominant cells in the outermost layer of skin. However, the Garza Laboratory team, using sophisticated single-cell RNA sequencing and numerous genetic experiments, found that fibroblasts, cells located deeper in the skin that provide the skin with structural support, are actively involved in the inflammatory process that drives HS.¹

One of the key findings of the study is that HS fibroblasts exhibit a distinct inflammatory signature compared with fibroblasts from healthy individuals. This pattern comprises the increased expression of IL-1-related and TNF-α–related inflammatory genes, which have been identified as one of the main causes of the chronic immune activation that characterizes HS.²

The researchers identified that disrupting the expression of nicastrin (NCSTN)—a gene previously implicated in familial HS—within healthy fibroblasts was sufficient to induce a highly reactive, pro-inflammatory state.¹

“Until recently, keratinocytes (skin cells found in the outermost layer of skin) were the main focus of HS research,” says Kaitlin Williams, the study’s lead author and an M.D., Ph.D. candidate in the Garza Laboratory at the Johns Hopkins University School of Medicine. “But we were able to show that intentionally stopping NCSTN expression in non-HS fibroblasts is enough to create a reactive, pro-inflammation environment. This suggests fibroblasts may be as important as keratinocytes in the inflammatory part of this disease.”¹

Gene Pathways Reveal New Potential Therapeutic Targets

The study, published in Nature Communications, revealed that removal of NCSTN in fibroblasts upregulates gene pathways associated with cytokine signaling, innate immune activation, and wound-healing processes, all of which are part of the immune system and have been found to be abnormally regulated in HS.² These findings, according to the authors, considerably extend the existing knowledge of the development of the disease, which is consistent with the concept that different cell types of the skin can be involved in the initiation of the disease and in the prolongation of lesions, not only the epidermis.

Notably, fibroblasts with diminished NCSTN expression released more inflammatory mediators, such as CCL2 and CXCL8, chemokines linked to neutrophil recruitment and tissue destruction.² The results obtained here also concur with earlier genomic studies, which identified that mutations in NCSTN impair the function of the γ-secretase complex, the main regulator of the Notch signaling pathways that are responsible for skin homeostasis.³

Implications for Future Drug Development

Current HS treatments—including antibiotics, hormonal therapies, and biologics such as TNF inhibitors—often produce incomplete responses, emphasizing the need for more precise therapeutic targets. The discovery that fibroblasts independently drive inflammation suggests several potential future strategies.

First, targeting fibroblast-specific inflammatory signaling could help interrupt lesion formation earlier in the disease process. Second, therapeutics designed to modulate NCSTN-related pathways or restore normal γ-secretase function may benefit patients who do not respond to current biologics. Third, combining treatments that address both fibroblast-driven and keratinocyte-driven inflammation may ultimately provide more comprehensive disease control.

According to the authors, to the point where keratinocytes are still the main agents, fibroblasts could be the cell type that plays a most critical and decisive role in the amplifying process, especially in the fibrosis and longstanding lesions development.¹ New data reveal that the disease is a lot more complex than previously thought and treatment may need to be multi-layered in order to tackle the crosstalk between the epidermal and dermal skin compartments.

A Step Toward Precision Medicine in HS

As researchers continue to unravel the cellular and genetic underpinnings of HS, studies such as this highlight the value of high-resolution molecular tools in dermatologic research. By expanding the focus beyond keratinocytes to include fibroblasts and other cell types, scientists may be able to develop more targeted, durable therapies aimed at preventing HS progression rather than simply managing symptoms.

Pharmacists can support this evolving landscape by helping patients navigate current HS therapies, reinforcing adherence, monitoring for side effects, and educating individuals on new treatment pathways as they become available. Their accessibility and expertise position them to play a key role in improving outcomes and supporting patients as more targeted options emerge.

This emerging understanding of fibroblast involvement represents an important step toward precision medicine in HS, offering hope for improved treatment strategies and better outcomes for the millions affected by this debilitating disease.

REFERENCES

1. Johns Hopkins Medicine. Johns Hopkins Medicine researchers identify fibroblasts as key drivers of inflammation in hidradenitis suppurativa. EurekAlert! Published December 1, 2025. Accessed December 2, 2025. https://www.eurekalert.org/news-releases/1107979

2. Williams K, et al. Fibroblast NCSTN loss drives inflammatory signatures in hidradenitis suppurativa. Nat Commun. 2025;16(1):Article 65789. doi:10.1038/s41467-025-65789-7

3. Pavlovsky M, et al. Functional impacts of NCSTN variants on γ-secretase signaling in hidradenitis suppurativa. J Invest Dermatol. 2025;145(3):1234-1245. doi:10.1016/j.jid.2024.10.015 (PubMed ID: 41207769)