Non-small cell lung cancer (NSCLC) is the deadliest cancer worldwide, killing more than 80% of patients within five years of diagnosis. Aberrant TRIM protein expression is known to play an important role in NSCLC, but the mechanisms aren’t clear. To learn more, a recent study investigated TRIM15 dysregulation in NSCLC. In a tissue microarray, TRIM15 was upregulated in NSCLC versus control tissues, and high TRIM15 expression was associated with a poor prognosis. In vitro, TRIM15 knockdown in NSCLC cells decreased cell proliferation, migration, and invasion, while TRIM15 overexpression exerted the opposite effects, which were dependent on the RING domain with E3 ubiquitin ligase activity. Similar results of TRIM15 silencing and overexpression were obtained in vivo in a subcutaneous xenograft mouse model. Mechanistic experiments revealed that TRIM15 ubiquitinated Keap1, targeting it for degradation. The resulting Keap1 breakdown allowed the Keap1 target Nrf2 to escape degradation, thus promoting tumor progression. Although more research on related pathways is needed, this study clarifies the pathological role of TRIM15 in NSCLC and suggests that the TRIM15–Keap1 interaction might be a valuable therapeutic target for this deadly cancer.