Background <p>Keloid fibrosis is characterized by aberrant fibroblast activation and excessive collagen accumulation following cutaneous injury. This study investigates the mechanism by which LncRNA RNF144A-AS1 promotes keloid fibrosis by mediating H4K5 acetylation, providing potential targets for developing novel therapeutic interventions.</p> Methods <p>Keloid fibroblasts were transfected with si-RNF144A-AS1, followed by detection of RNF144A-AS1, HUR, P300, and PDE4 expression. The levels of TNF-α, TGF-β1, and IL-1β were measured by ELISA. The expression of α-SMA, COL1A1, HUR, P300, and PDE4 was assessed by western blot. The binding between RNF144A-AS1 and HUR was validated using RIP and RNA pull-down assays. Actinomycin D treatment was used to assess P300 mRNA stability. The enrichment of P300 and H4K5ac on the PDE4 promoter was detected by Ch-IP. Combined experiments were used to verify the role of RNF144A-AS1 in keloid fibrosis via the P300/PDE4 axis. Bleomycin sulfate-induced keloid mouse models were established. After silencing RNF144A-AS1 in mice, the skin tissue changes, dermal thickness, and collagen deposition were evaluated. α-SMA and TGF-β1 expression was detected by IHC.</p> Results <p>RNF144A-AS1 was highly expressed in keloid fibrosis cell models. RNF144A-AS1 downregulation reduced cell viability and decreased the expression of TGF-β1, TNF-α, IL-1β, α-SMA, and COL1A1. RNF144A-AS1 bound to HUR to promote P300 expression. P300 upregulated histone H4K5 acetylation on the PDE4 promoter, enhancing PDE4 expression. Overexpression of P300 or PDE4 partially reversed the inhibitory effects of RNF144A-AS1 knockdown on keloid fibrosis. Silencing RNF144A-AS1 suppressed keloid fibrosis in vivo.</p> Conclusions <p>RNF144A-AS1 drives keloid fibrosis through P300-mediated H4K5 acetylation of PDE4.</p>