PDLIM4 drives gastric cancer malignant progression and cisplatin resistance by inhibiting HSP70 ubiquitination and degradation via competitive interaction with STUB1.

Gastric cancer (GC) frequently shows malignant progression and resistance to chemotherapy due to complex molecular regulatory processes, leading to a poor prognosis. Our study elucidates that PDZ and LIM domain protein 4 (PDLIM4) are highly expressed in GC, thereby promoting the malignant progression and cisplatin (DDP) resistance of GC. Mechanistically, PDLIM4, via its C-terminal and intermediate regions, impedes the ubiquitination and proteasomal degradation of Heat Shock Protein 70 (HSP70) by competing with the STIP1 homology and U-box containing protein 1 (STUB1), subsequently activating the MAPK signaling pathway. In addition, we synthesized lipid nanoparticles (LNPs), including siPDLIM4 LNPs, DDP LNPs, and siPDLIM4/DDP LNPs. Experiments further indicated that siPDLIM4 LNPs and DDP LNPs have an anti-tumor property, while siPDLIM4/DDP LNPs exhibit the most significant anti-tumor efficacy. In summary, our research identifies PDLIM4 as a facilitator of malignant progression and DDP resistance in GC cells, targeting PDLIM4 not only inhibits the malignant progression of GC, but also provides an effective strategy to enhance DDP sensitivity in GC treatment, emphasizing its potential as a therapeutic target.