Molecular Subtypes of Balanopreputial and Urethral Male Genital Lichen Sclerosus: Distinct Transcriptomic and Clinicopathological Profiles.

Male genital lichen sclerosus (MGLSc) is a heterogeneous and aggressive disease characterized by varying severities of balanopreputial and urethral disease (MGLSc-US) and outcomes, including stricture. This study aims to elucidate the transcriptomic heterogeneity of MGLSc and explore its associations with histological and clinical features. We collected 40 preputial samples and 14 urethral tissue samples from patients with MGLSc-US, non-MGLSc urethral strictures, and redundant prepuce. Bulk RNA sequencing was performed to comprehensively profile the transcriptome. Molecular subtypes, functional features, and gene signatures were identified in MGLSc prepuce and urethral lesions. Additionally, we examined the histological and clinical features specific to each subtype. Two distinct transcriptomic subtypes in preputial lesions were identified. Subtype 1 was characterized by the upregulation of immune pathways and increased lymphocytic stromal infiltration. Subtype 2 showed an upregulation of epithelial cell proliferation and cellular stress response pathways. Both subtypes demonstrated features of hyperkeratosis; however, atrophy was specifically associated with subtype 1, whereas subtype 2 showed significant downregulation of extracellular matrix organization pathways and milder dermal sclerosis. PLEK, PIK3AP1, NCF1, CTSS, and SELL and EVPL, RAPGEFL1, and TMEM79 were identified as 2 subtype gene signatures across preputial and urethral lesion cohorts. Clinically, subtype 2 was significantly associated with longer US segments compared with subtype 1. This study provides the first detailed transcriptomic characterization of MGLSc, identifying 2 distinct molecular subtypes with stratified markers. These findings offer a foundation for clinical and molecular classification of MGLSc and may guide management strategies and novel therapeutic developments for this challenging condition.