biostudies-literatureYun FNational Natural Science Foundation of ChinaNational Natural Science Foundation of China (National Science Foundation of China)720https://www.ebi.ac.uk/biostudies/studies/S-EPMC11445241biostudies-literatureUnknown15(10)Nucleotide-binding oligomerization domain 2 (NOD2) is an immune sensor crucial for eliciting the innate immune responses. Nevertheless, discrepancies exist regarding the effect of NOD2 on different types of cancer. This study aimed to investigate these function of NOD2 in melanoma and its underlying mechanisms. We have validated the tumor suppressor effect of NOD2 in melanoma. NOD2 inhibited the proliferation of melanoma cells, hindering their migration and invasion while promoting the onset of apoptosis. Our study showed that NOD2 expression is closely related to pyrimidine and folate metabolism. NOD2 inhibits thymidylate synthase (TYMS) expression by promoting K48-type ubiquitination modification of TYMS, thereby decreasing the resistance of melanoma cells to 5-fluorouracil (5-FU) and caCell death & diseaseNOD2 reduces the chemoresistance of melanoma by inhibiting the TYMS/PLK1 signaling axis.PMC11445241819604628176045582160540821033883196014531960200Yi XSai BYun FWu NZhu YLi EFeng YNi QKuang YZhang QYang ZZhang XGai YfalseNOD2 reduces the chemoresistance of melanoma by inhibiting the TYMS/PLK1 signaling axis.Nucleotide-binding oligomerization domain 2 (NOD2) is an immune sensor crucial for eliciting the innate immune responses. Nevertheless, discrepancies exist regarding the effect of NOD2 on different types of cancer. This study aimed to investigate these function of NOD2 in melanoma and its underlying mechanisms. We have validated the tumor suppressor effect of NOD2 in melanoma. NOD2 inhibited the proliferation of melanoma cells, hindering their migration and invasion while promoting the onset of apoptosis. Our study showed that NOD2 expression is closely related to pyrimidine and folate metabolism. NOD2 inhibits thymidylate synthase (TYMS) expression by promoting K48-type ubiquitination modification of TYMS, thereby decreasing the resistance of melanoma cells to 5-fluorouracil (5-FU) and ca2024-01-01T00:00:00Z2024 Oct2026-06-02T18:41:46.942Z2025-04-04T11:03:56.843ZS-EPMC114452413935390410.1038/s41419-024-07104-8