Multiple myeloma (MM) is an incurable plasma cell malignancy with limited therapeutic options. Although autophagy dysregulation is implicated in MM pathogenesis, its precise regulation, particularly by circular RNAs (circRNAs), is poorly understood. Through clinical RNA sequencing of primary MM patient samples, we identify an autophagy-associated circRNA, circ_0008255, which is markedly upregulated in MM patients and closely correlated with poor disease prognosis. Functional studies reveal that circ_0008255 promotes MM proliferation and tumor growth by enhancing autophagic activity. Mechanistically, it functions as a competitive endogenous RNA for miR-192-5p, leading to elevated expression of the core autophagy protein, autophagy related 2 homolog A (ATG2A). Furthermore, we developed a biomimetic nanoplatform based on layered double hydroxide (LDH) nanosheets coated with myeloma-derived cell membranes for tumor-specific delivery. This system co-delivers siRNA targeting circ_0008255 to suppress autophagosome initiation, while simultaneously leveraging the lysosome-alkalinizing property of LDH to impair autophagosome–lysosome fusion. Together, these actions enforce a synergistic autophagic full-chain blockade, leading to potent antitumor effects in vitro and in vivo. Overall, our study reveals a central regulatory role of circ_0008255 in myeloma autophagy, offering a promising therapeutic paradigm for MM.
Zhenhua Wang, Hefei Ren, Kun Wang et al.· Bioactive Materials· 0 citations
Background and aim Lactylation is a novel histone modification driven by lactate accumulation, which has been implicated in clear cell renal cell carcinoma (ccRCC) progression. However, its comprehensive molecular mechanism and clinical relevance remain poorly understood. This study aimed to investigate lactylation-related molecular mechanisms and therapeutic responses in ccRCC using integrated single-cell analysis and machine learning algorithms. Methods We integrated single-cell RNA sequencing and bulk transcriptomic data from patients with ccRCC. Transcriptional signatures of lactylation-related genes were evaluated using four gene set scoring algorithms. Key lactylation-related genes were identified through weighted gene co-expression network analysis and differential expression analysis. A prognostic model was constructed using 10 machine learning algorithms and subsequently validated in independent cohorts. The functional role of the core gene, CDT1, was validated through in vitro and in vivo experiments. Results We established a prognostic model comprising 13 lactylation-related genes. The model robustly stratified patients into high- and low-risk groups with distinct survival outcomes, immune microenvironment features, and immunotherapy responses. Functional assays revealed that CDT1, the core gene of the signature, promoted ccRCC cell proliferation, migration, and invasion. Moreover, modulation of CDT1 altered intracellular L-lactate levels. However, whether this effect reflects a direct metabolic–epigenetic regulatory mechanism or is secondary to proliferative changes remains to be elucidated. Conclusions This study delineates the molecular heterogeneity associated with lactylation-related gene expression in ccRCC and presents a validated prognostic model. It identifies CDT1 as a novel oncogene and potential biomarker, providing insights into metabolic–epigenetic crosstalk and a foundation for future therapeutic development.
Yue Zhang, Hang Zhou, Bihui Zhang et al.· Frontiers in Endocrinology· 0 citations
