Targeting Macrophage-to-Myofibroblast Transition Mitigates Progression from Inflammation to Fibrosis in Rosacea

TL;DR

This study shows that macrophages in rosacea can transform into myofibroblasts, causing fibrosis, and identifies a natural compound that may help treat the condition.

Contribution

The study identifies macrophage-to-myofibroblast transition (MMT) as a novel driver of fibrosis in rosacea and proposes Bruceine A as a dual-acting therapeutic candidate.

Findings

Macrophages in rosacea acquire myofibroblast-like features through MMT, contributing to fibrotic remodeling.

Bruceine A suppresses fibrotic remodeling by targeting STAT3 palmitoylation and reducing MMT.

Macrophage depletion alleviates fibrotic remodeling in LL37-induced mouse models.

Abstract

Rosacea is a globally prevalent chronic inflammatory skin disorder that markedly impairs quality of life, yet treatment options are limited. A characteristic feature of rosacea is macrophage infiltration, whose role in disease pathogenesis remains incompletely understood beyond inflammation; here, we identify their contribution to fibrotic remodeling through macrophage-to-myofibroblast transition (MMT). Serum proteomics revealed that TGF-β1 was prominently elevated in rosacea patients. Moreover, single-cell RNA sequencing (scRNA-seq), spatial transcriptomics (ST), and histological staining of skin biopsies demonstrated that fibrotic remodeling was already evident at inflammation-dominant stages, with macrophages progressively acquiring myofibroblast-like features through MMT. These observations were recapitulated in LL37-induced mouse models by scRNA-seq and ST, further validated by lineage tracing using Cx3cr1-GFP knock-in mice. Interestingly, macrophage depletion markedly alleviated LL37-induced fibrotic remodeling, underscoring the pathogenic role of MMT. Through integrative screening, we subsequently identified Bruceine A (BA), a natural quassinoid that suppressed fibrotic remodeling by reducing MMT and attenuating keratinocyte-driven inflammation in vivo. BA directly targeted STAT3 and interfered with its palmitoylation-dependent activation, thereby disrupting profibrotic and inflammatory signaling. Our findings establish MMT as a driver of fibrotic remodeling in rosacea, define STAT3 palmitoylation as a therapeutic target, and position BA as a dual-acting candidate for mechanism-based intervention.

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