LncRNA OLMALINC promotes osteosarcoma progression through USP1-mediated autophagy suppression

Osteosarcoma (OS) remains a challenging malignancy with poor prognosis, especially in metastatic or recurrent cases. Despite progress, the molecular mechanisms driving OS, particularly the regulation of autophagy, are not fully understood. Here, through integrated analysis of single-cell and transcriptomic data, we identify a novel long non-coding RNA (lncRNA), OLMALINC, as a critical autophagy regulator in OS. OLMALINC is significantly upregulated in OS tissues, with its expression correlating to poor clinical outcomes. Functional studies show that altering OLMALINC expression impacts OS cell progression and autophagy. Mechanistically, transcriptome analysis and RNA immunoprecipitation reveal Ubiquitin-Specific Peptidase 1 (USP1) as a direct downstream target of OLMALINC. The OLMALINC-USP1 axis inhibits autophagy and activates the hypoxia-inducible factor 1 (HIF-1α) pathway, promoting OS progression. Therapeutically, combining the USP1 inhibitor ML-323 with doxorubicin demonstrated synergistic anti-tumor effects in vitro and in vivo, enhancing autophagy and apoptosis while inhibiting tumor growth. These findings uncover a novel OLMALINC-USP1-HIF-1α axis in OS progression and highlight the potential of combining autophagy modulation with chemotherapy for improved therapeutic outcomes.