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Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer with poor prognosis. This study designated to figure out the effects of Ubiquitin Specific Peptidase 36 (USP36) on NSCLC. Data of this study demonstrated that upregulation of USP36 was observed in NSCLC tissues and cell lines. Overexpression of USP36 promoted NSCLC cell proliferation and inhibited NSCLC cell apoptosis. Knockdown of USP36 decreased Ketohexokinase A (KHK-A) and increased KHK-C expression at both RNA and protein levels. Expression of c-MYC and hnRNPH1/H2 was positively correlated with the expression of USP36. Upregulation of c-MYC reversed the downregulation of hnRNPH1/H2 induced inhibition of USP36. Overexpression of hnRNPH1/H2 reversed the downregulation of KHK-A induced inhibition of USP36. Results of in vivo xenograft model were consistent with the findings of in vitro experiments. In summary, overexpression of USP36 in NSCLC accelerated tumor growth through upregulation of KHK-A, which was medicated by stabilizing c-MYC to increase hnRNPH1/H2 expression. [ABSTRACT FROM AUTHOR]