ALDH2 regulates oxaliplatin sensitivity via PDE4B in p53-mutant colorectal cancer.

Background: Chemoresistance remains a major limitation in the treatment of colorectal cancer (CRC), particularly in tumors harboring TP53 mutations. Although aldehyde dehydrogenase 2 (ALDH2) has been implicated in cancer biology, its role in regulating platinum sensitivity and the underlying molecular context remain incompletely understood. Methods: Public transcriptomic and proteomic datasets (TCGA, GEO, CPTAC) were analyzed to evaluate ALDH2 expression patterns, prognostic relevance, and associations with chemotherapy response in CRC. Functional studies were performed in p53-mutant and p53-wild-type CRC cell lines using pharmacological inhibition and genetic silencing of ALDH2, complemented by p53 knockout and reconstitution approaches. Downstream signaling was interrogated by gene set enrichment analysis, quantitative PCR, and pharmacological inhibition of phosphodiesterase 4B (PDE4B). Oxaliplatin sensitivity was assessed using cell viability and apoptosis assays. Results: ALDH2 expression was significantly reduced in CRC tissues and was associated with unfavorable clinical outcomes and diminished oxaliplatin responsiveness. Functional experiments revealed that inhibition or knockdown of ALDH2 selectively induced oxaliplatin resistance in p53-mutant CRC cells, while p53-wild-type cells were largely unaffected. Mechanistically, loss of ALDH2 led to upregulation of PDE4B in a p53 status-dependent manner. Elevated PDE4B expression correlated with chemoresistance and poor recurrence-free survival in patients with p53-mutant CRC. Importantly, pharmacological inhibition of PDE4B using the clinically approved drug roflumilast effectively restored oxaliplatin-induced apoptosis and reversed chemoresistance in ALDH2-deficient, p53-mutant CRC cells. Conclusions: This study identifies a previously unrecognized, p53 status-dependent ALDH2-PDE4B regulatory axis that governs oxaliplatin sensitivity in colorectal cancer. Our findings highlight ALDH2 as a potential predictive biomarker for oxaliplatin response in p53-mutant CRC and suggest that targeting PDE4B may represent a promising strategy to overcome chemoresistance in this molecular context.