| Summary: | Background: The treatment of non‐small‐cell lung cancer (NSCLC) involves platinum-based chemotherapy. It is typically accompanied by chemoresistance resulting from antioxidant properties conferred by cancer stem cells (CSCs). Human epidermal growth factor receptor 2 (HER2) enhances CSCs and antioxidant properties in cancers, including NSCLC. Methods: Here, we elucidated the role of histamine N‐methyltransferase (HNMT), a histamine metabolism enzyme significantly upregulated in NSCLC and coexpressed with HER2. HNMT expression in lung cancer tissues was determined using quantitative reverse transcription PCR (RT‐qPCR). A publicly available dataset was used to determine HNMT’s potential as an NSCLC target molecule. Immunohisto-chemistry and coimmunoprecipitation were used to determine HNMT–HER2 correlations and in-teractions, respectively. HNMT shRNA and overexpression plasmids were used to explore HNMT functions in vitro and in vivo. We also examined miRNAs that may target HNMT and investigated HNMT/HER2′s role on NSCLC cells’ antioxidant properties. Finally, how HNMT loss affects NSCLC cells’ sensitivity to cisplatin was investigated. Results: HNMT was significantly upregu-lated in human NSCLC tissues, conferred a worse prognosis, and was coexpressed with HER2. HNMT depletion and overexpression respectively decreased and increased cell proliferation, colony formation, tumorsphere formation, and CSCs marker expression. Coimmunoprecipitation analysis indicated that HNMT directly interacts with HER2. TARGETSCAN analysis revealed that HNMT is a miR‐223 and miR‐3065‐5p target. TBHp treatment increased HER2 expression, whereas shHNMT disrupted the Nuclear factor erythroid 2‐related factor 2 (Nrf2)/ hemeoxygenase‐1 (HO‐ 1)/HER2 axis and increased reactive oxygen species accumulation in NSCLC cells. Finally, shHNMT sensitized H441 cells to cisplatin treatment in vitro and in vivo. Conclusions: Therefore, HNMT up-regulation in NSCLC cells may upregulate HER2 expression, increasing tumorigenicity and chemo-resistance through CSCs maintenance and antioxidant properties. This newly discovered regulatory axis may aid in retarding NSCLC progression and chemoresistance.
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