The biology function of antisense intronic long noncoding RNA (Ai-lncRNA) is still unknown. Meanwhile, cancer patients with paclitaxel resistance have limited therapeutic options in the clinic. However, the potential involvement of Ai-lncRNA in paclitaxel sensitivity remains unclear in human cancer. Whole transcriptome sequencing of 33 breast specimens was performed to identify Ai-lncRNA EGOT. Next, the role of EGOT in regulation of paclitaxel sensitivity was investigated. Moreover, the mechanism of EGOT enhancing autophagy sensitizes paclitaxel cytotoxicity via upregulation of ITPR1 expression by RNA-RNA and RNA-protein interactions was investigated in detail. Furthermore, upstream transcriptional regulation of EGOT expression was also investigated by co-immunoprecipitation and chromatin immunoprecipitation. Finally, clinical breast specimens in our cohort, TCGA and ICGC were applied to validate the role of EGOT in enhancing of paclitaxel sensitivity. EGOT enhances autophagosome accumulation via the up-regulation of ITPR1 expression, thereby sensitizing cells to paclitaxel toxicity. Mechanistically, on one hand, EGOT upregulates ITPR1 levels via formation of a pre-ITPR1/EGOT dsRNA that induces pre-ITPR1 accumulation to increase ITPR1 protein expression in cis. On the other hand, EGOT recruits hnRNPH1 to enhance the alternative splicing of pre-ITPR1 in trans via two binding motifs in EGOT segment 2 (324–645 nucleotides) in exon 1. Moreover, EGOT is transcriptionally regulated by stress conditions. Finally, EGOT expression enhances paclitaxel sensitivity via assessment of cancer specimens. These findings broaden comprehensive understanding of the biology function of Ai-lncRNAs. Proper regulation of EGOT may be a novel synergistic strategy for enhancing paclitaxel sensitivity in cancer therapy.

Non-coding RNA activated by DNA damage (NORAD) has been found to enhance proliferation and metastasis of cancer cells. Ferroptosis is characterized by excess lipid peroxidation and has been confirmed to eliminate cancer cells. However, the specific role of NORAD in cancer and ferroptosis is not clear. In this study, data from public databases were downloaded to investigate role of NORAD in cancer. NORAD expression was higher in cancer tissues than in normal and was positively related with worse survival of patients. NORAD was negatively related with effect of multiple anti-cancer agents. Epigenetic factors, including lower DNA methylation and EP300-induced higher histone acetylation resulted in enhanced expression of NORAD. GO and KEGG analysis showed that NORAD participated in lipid peroxidation and ROS metabolism, indicating that NORAD may serve as a role in ferroptosis. Indeed, in-vitro and in-vivo assays showed that expression of NORAD is negatively related with ferroptosis in cancer cells. Mechanically, NORAD competitively bound with miR-144-3p and resulted in up-regulation of mTOR which served as an inhibitor of ferritinophagy. Decreased ferritinophagy led to lower free iron ions and the following reduced ferroptosis. Inhibited ferroptosis by NORAD was expanded by autophagy inhibitor 3-MA and reversed by autophagy inducer EBSS. Lastly, application of anti-cancer treatment cisplatin, radiation, doxorubicin and PTX exhibited synergetic anti-cancer effect with NORAD knock-down, and NORAD over-expression attenuated anti-cancer effect of drugs. In total, NORAD is a promoter of oncogenesis and inhibited ferroptosis via miR-144-3p-mTOR-ferritinophagy in cancer cells.

Breast cancer remains the most common malignancy in women worldwide, and its marked heterogeneity continues to impede effective treatment. Immunotherapy has reshaped the therapeutic landscape, yet only a subset of patients achieves durable benefit, in large part because of immune and metabolic diversity within the tumor microenvironment. Posttranslational modifications are key regulators that couple cellular signaling to metabolic and immune homeostasis. Here, we generated a multiomics immune-metabolic atlas of breast cancer by integrating genomics, transcriptomics, proteomics, lactylomics, and phosphoproteomics from 115 tumor and 99 matched adjacent tissue samples. Using immune infiltration profiling, we defined 3 immune-related breast cancer subtypes with distinct metabolic states, posttranslational modifications cross-talk, and mutational landscapes. Integrated analyses revealed that the interplay between protein lactylation and phosphorylation orchestrates glycolytic reprogramming and immune modulation. Furthermore, we identified subtype-specific histone lactylation patterns and signaling rewiring associated with therapeutic response. This atlas provides a comprehensive framework for dissecting immune-metabolic regulation in breast cancer and yields molecular insights to guide subtype-specific precision immunotherapeutic strategies.