Δ40p53 plays a distinct regulatory role in maintaining cellular homeostasis by controlling SGSH expression via miR-4651-5p

ABSTRACT Δ40p53, the only translational isoform of p53, modulates the full-length p53 (FLp53) activity and independently regulates targets such as the miR-186-5p–YY1 axis. To identify additional miRNAs regulated by Δ40p53, we performed small RNA sequencing. We found that overexpression of Δ40p53, but not FLp53, significantly downregulated miR-4671-5p. Expression of both isoforms at varying ratios revealed that miR-4671-5p may be modulated by FLp53 in a Δ40p53-dependent manner. In silico analysis identified SGSH (N-sulfoglucosamine sulfohydrolase) as a potential miR-4671-5p target. SGSH expression showed inverse correlation with miR-4671-5p in cancer datasets and prognostic significance. SGSH mRNA and protein levels were reduced upon miR-4671-5p overexpression or siΔ40p53 treatment, confirming regulatory linkage. Functionally, miR-4671-5p overexpression induced intra-S-phase cell cycle arrest, implicating SGSH in cell cycle regulation. These results reveal a novel Δ40p53–miR-4671-5p–SGSH axis that impacts cell cycle progression and may contribute to cancer outcomes. Our findings highlight the distinct regulatory role of Δ40p53, independent of FLp53, in maintaining cellular and metabolic homeostasis via miRNA-mediated mechanisms.