Background: Keloid disorder manifests as the hyperproliferation of fibroblasts and resultant excessive scar formation, and the upregulation of the MyoD family inhibitor (MDFI) has been identified in keloids. Bioinformatics predictions further suggested an enrichment of sterol regulatory element binding transcription factor 2 (SREBF2) at the MDFI enhancer site. This study aimed to elucidate the specific roles and the potential regulatory axis of SREBF2 and MDFI in the proliferation of keloid fibroblasts (KFs).

Methods: The location of MDFI enhancer was predicted through bioinformatics. Chromatin immunoprecipitation followed by polymerase chain reaction was subsequently performed to quantify the enrichment of histone H3 lysine 27 acetylation (H3K27Ac) and SREBF2 at the MDFI enhancer in KFs derived from keloid dermis or normal skin fibroblasts (NFs) collected from adjacent healthy skin tissues. Following transfection as appropriate, proliferation, migration and invasion of KFs were determined through Ki67 staining, wound healing assay and Transwell assay, respectively. Western blot or quantitative real-time reverse transcription PCR analyses were applied to test the expression levels of MDFI, SREBF2, or apoptosis-related proteins (BCL2 associated X (Bax), BCL2 apoptosis regulator (Bcl-2)).

Results: MDFI and SREBF2 expression levels were upregulated in keloid dermis (p < 0.05). SREBF2 was enriched in the enhancer region of MDFI, and its silencing suppressed MDFI expression in KFs (p < 0.05). MDFI overexpression promoted proliferation, migration and invasion, elevated Bcl-2 expression in KFs, but suppressed Bax expression, whereas MDFI silencing did conversely (p < 0.05). SREBF2 silencing repressed proliferation, migration and invasion, diminished Bcl-2 expression in KFs, but augmented Bax expression, which was counteracted by overexpressed MDFI (p < 0.05).

Conclusion: This study demonstrates that SREBF2 promotes KF proliferation, migration and invasion, and inhibits apoptosis by activating MDFI through binding to MDFI enhancer transcription. The identified SREBF2/MDFI axis presents a novel potential therapeutic target for mitigating keloid progression.