Lung cancer, classified into non-small cell lung carcinoma (NSCLC) and small cell lung carcinoma (SCLC), presents a significant challenge in the realm of global health due to its high incidence, elevated recurrence rates, and substantial mortality. NSCLC constitutes the predominant subtype, accounting for approximately 85% of all lung cancer cases, thereby establishing it as the most prevalent form of lung cancer [1]. In the last ten years, non-surgical treatments for NSCLC have greatly improved, especially with targeted therapies, significantly increasing patient survival and offering new hope [2]. Nonetheless, a subset of patients remains without identifiable driver mutations. Furthermore, some patients, despite possessing genetic mutations, develop resistance to targeted therapies within months, resulting in a poor prognosis [3]. As a result, there is still a need to investigate the unexplored molecular mechanisms in NSCLC to identify new targets for therapy.

The mitochondrial ribosomal proteins (MRPs), encoded by nuclear genes and assembled within mitochondria, constitute a crucial component of the mitochondrial ribosome, facilitating the translation of 13 proteins encoded by mitochondrial DNA [4]. These proteins are indispensable for the mitochondrial respiratory chain [5]. Given that metabolic reprogramming is a hallmark of lung cancer, dysregulation of MRPs may result in altered energy metabolism, thereby promoting the rapid proliferation and survival of cancer cells [6]. Recent studies have underscored the significance of MRPs in cancer biology, demonstrating alterations in their expression patterns across various cancer types and highlighting their potential as prognostic biomarkers and therapeutic targets [7], [8], [9]. Studying MRPs in various cancers can uncover mechanisms of disease progression, offering new treatment insights. Targeting MRPs alongside mitochondrial biogenesis could be a promising anticancer strategy.

The present study identified mitochondrial ribosomal protein L2 (MRPL2) as a potential anti-tumor therapeutic target that is upregulated in NSCLC and is associated with poor prognosis. Mechanistic studies reveal that USP21 can interact with MRPL2 and increase its protein stability by deubiquitination. Subsequently, nuclear-localized MRPL2, but not conventionally mitochondrial-localized MRPL2, can facilitate calcium signaling by colocalizing with programmed cell death 11 (PDCD11) in the nucleus, ultimately contributing to NSCLC development. Furthermore, we conducted a screening of lometrexol as a potential inhibitor of MRPL2. This study reveals a novel role for the USP21/MRPL2/PDCD11/Ca2+ axis in NSCLC progression, providing a promising target for the treatment of NSCLC.