CKS2 Silencing Affects Proliferation and Apoptosis in Multiple Myeloma through the PTEN/ AKT/mTOR Pathway.

Multiple myeloma (MM), a prevalent plasma cell malignancy, represents a life-threatening hematological disorder with significant clinical morbidity. Despite its recognized impact on global health burdens, the precise molecular pathogenesis underlying disease progression remains incompletely elucidated. Transcriptomic profiling via RNA sequencing revealed significant upregulation of cyclin-dependent kinase regulatory subunit 2 (CKS2) in multiple myeloma. Clinical validation was performed through quantitative analysis of CKS2 expression in patient-derived specimens. Two established MM cell models (MM.1S and RPMI-8226) were selected for functional characterization. Cellular proliferation dynamics were quantified using CCK-8 metabolic assays and EdU DNA incorporation analysis, with flow cytometric evaluation employed to assess apoptotic indices. A xenograft mouse model was established to investigate CKS2-mediated tumorigenesis in vivo, complemented by western blot analysis of pathway-associated protein expression. Bioinformatic interrogation of the HumanBase database identified putative CKS2 interactomes, subsequently validated through co-immunoprecipitation assays and confocal immunofluorescence microscopy. Structural modeling via AlphaFold2 predicted molecular interaction interfaces, with three-dimensional visualization achieved through PyMOL rendering. In this study, we demonstrated that CKS2 knockdown in MM.1S and RPMI-8226 cell lines significantly inhibited cellular proliferation and induced apoptosis. Conversely, CKS2 overexpression enhanced malignant proliferation while suppressing apoptotic processes, establishing its functional role in myeloma pathogenesis. Mechanistic investigations revealed that CKS2 depletion modulates cell proliferation and apoptosis via PTEN/AKT/mTOR signaling axis. Notably, co-immunoprecipitation assays demonstrated direct protein-protein interaction between CKS2 and thioredoxin (TXN), with subsequent functional validation suggesting TXN appears to function as a key upstream regulatory factor governing CKS2 stability. These findings establish CKS2 as a critical regulator of myeloma cell homeostasis and identify it as a promising therapeutic target warranting further preclinical validation.