在这项研究中，发现长链非编码RNA、DNA损伤诱导转录4反义RNA1（DDIT4-AS1）在三阴性乳腺癌（TNBC）细胞系和组织中高表达，由于启动子区域的H3K27乙酰化，并通过激活自噬促进TNBC细胞的增殖、迁移和侵袭。在机制上，研究表明，DDIT4-AS1通过稳定DDIT4 mRNA、招募RNA结合蛋白AUF1并促进DDIT4 mRNA和AUF1之间的相互作用，从而抑制mTOR信号通路，诱导自噬。此外，沉默DDIT4-AS1可增强TNBC细胞对紫杉醇等化疗药物在体外和体内的敏感性。使用自激活siRNA/药物核壳纳米粒子系统，有效地将DDIT4-AS1 siRNA和紫杉醇同时传递至肿瘤携带小鼠体内，从而达到显著的抗肿瘤活性。更重要的是，联合输送纳米粒子对乳腺癌患者来源的器官样球体具有更强的抗肿瘤效果。这些发现表明，lncRNA DDIT4-AS1介导的自噬激活促进了TNBC的进展和化疗耐药，并且DDIT4-AS1的靶向可能被作为增强化疗药物对抗TNBC的新治疗方法。© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.

In this study, it is found that the lncRNA, DNA damage inducible transcript 4 antisense RNA1 (DDIT4-AS1), is highly expressed in triple-negative breast cancer (TNBC) cell lines and tissues due to H3K27 acetylation in the promoter region, and promotes the proliferation, migration, and invasion of TNBC cells via activating autophagy. Mechanistically, it is shown that DDIT4-AS1 induces autophagy by stabilizing DDIT4 mRNA via recruiting the RNA binding protein AUF1 and promoting the interaction between DDIT4 mRNA and AUF1, thereby inhibiting mTOR signaling pathway. Furthermore, silencing of DDIT4-AS1 enhances the sensitivity of TNBC cells to chemotherapeutic agents such as paclitaxel both in vitro and in vivo. Using a self-activatable siRNA/drug core-shell nanoparticle system, which effectively deliver both DDIT4-AS1 siRNA and paclitaxel to the tumor-bearing mice, a significantly enhanced antitumor activity is achieved. Importantly, the codelivery nanoparticles exert a stronger antitumor effect on breast cancer patient-derived organoids. These findings indicate that lncRNA DDIT4-AS1-mediated activation of autophagy promotes progression and chemoresistance of TNBC, and targeting of DDIT4-AS1 may be exploited as a new therapeutic approach to enhancing the efficacy of chemotherapy against TNBC.© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.