Disruption of the ∆40p53/ miR ‐4671‐5p/ SGSH axis results in intra‐S‐phase arrest and poor cancer prognosis

Parsing the functions of the tumor suppressor tumor protein p53 ( TP53 ) is complex due to the multiple isoforms it encodes. ∆40p53, an N‐terminally truncated p53 isoform and the only translational isoform, modulates full‐length p53 (FLp53) activity and independently regulates targets such as the miR‐186‐5p/transcriptional repressor protein YY1 axis. To identify additional miRNAs regulated by ∆40p53, we performed small RNA sequencing. We found that ectopic overexpression of ∆40p53, 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 ∆40p53‐dependent manner. In silico analysis identified N‐sulfoglucosamine sulfohydrolase ( SGSH ) as a potential miR‐4671‐5p target. SGSH expression showed an inverse correlation with miR‐4671‐5p in cancer datasets and had prognostic significance. SGSH mRNA and protein levels were reduced upon miR‐4671‐5p overexpression or si∆40p53 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 previously unknown ∆40p53/miR‐4671‐5p/ SGSH axis that, when dysregulated, induces intra‐S‐phase cell cycle arrest and may contribute to cancer outcomes. Our findings highlight the distinct regulatory role of ∆40p53, independent of FLp53, in maintaining cellular and metabolic homeostasis via miRNA‐mediated mechanisms.