尽管乳腺癌治疗取得了进展，但仍有相当一部分患者由于耐药性而复发。 microRNA 在癌症进展和化疗反应中的参与已得到充分证实。因此，本研究旨在阐明 microRNA-449 家族（特别是 microRNA-449a、microRNA-449b-5p 和 microRNA-449c-5p）的失调及其对阿霉素（一种常用化疗药物）耐药性的影响。三阴性乳腺癌的治疗。我们发现 microRNA-449 家族在三阴性乳腺癌中表达下调，并证明了其作为诊断生物标志物的潜力。此外，我们的研究结果表明 microRNA-449 家族的下调是由 microRNAs-449/SIRT1-HDAC1 负反馈环介导的。此外，研究发现 microRNA-449 家族通过靶向 ACSL4 来失调脂肪酸代谢，ACSL4 是一种潜在的预后生物标志物，通过调节药物挤出泵 ABCG2 介导阿霉素反应。总而言之，我们的结果表明 microRNA-449 家族可能是治疗三阴性乳腺癌的潜在治疗靶点，因为它通过 ACSL4/ABCG2 轴调节参与阿霉素反应。最终，我们的结果还强调了 microRNAs-449 和 ACSL4 作为三阴性乳腺癌诊断和预后生物标志物的价值。提出的 TNBC 和阿霉素反应中 miRNA-449 下调的模型。 MiRNA-449 在 TNBC 中通过 SIRT1 和 HDAC1 的负反馈环路下调。此外，ACSL4 增加 ABCG2 表达，从而降低细胞内阿霉素浓度并促进阿霉素耐药。 miRNA-449 过表达下调 ACSL4/ABCG2 轴并使阿霉素耐药细胞对阿霉素敏感。使用 BioRender 创建。 TNBC：三阴性乳腺癌； DOX：阿霉素； SIRT1: Sirtuin 1; HDAC1：组蛋白脱乙酰酶 1； ACSL4：酰基辅酶A合成酶长链家族成员4； ABCG2：ATP 结合盒超家族 G 成员 2。© 2024。作者。

Despite progress in breast cancer treatment, a significant portion of patients still relapse because of drug resistance. The involvement of microRNAs in cancer progression and chemotherapy response is well established. Therefore, this study aimed to elucidate the dysregulation of the microRNA-449 family (specifically, microRNA-449a, microRNA-449b-5p, and microRNA-449c-5p) and its impact on resistance to doxorubicin, a commonly used chemotherapeutic drug for the treatment of triple-negative breast cancer. We found that the microRNA-449 family is downregulated in triple-negative breast cancer and demonstrated its potential as a diagnostic biomarker. Besides, our findings indicate that the downregulation of the microRNA-449 family is mediated by the microRNAs-449/SIRT1-HDAC1 negative feedback loop. Moreover, it was found that the microRNA-449 family dysregulates the fatty acid metabolism by targeting ACSL4, which is a potential prognostic biomarker that mediates doxorubicin response through regulation of the drug extrusion pump ABCG2. Altogether, our results suggest that the microRNA-449 family might be a potential therapeutic target for the treatment of triple-negative breast cancer since it is implicated in doxorubicin response through ACSL4/ABCG2 axis regulation. Ultimately, our results also highlight the value of microRNAs-449 and ACSL4 as diagnostic and prognostic biomarkers in triple-negative breast cancer. Proposed model of miRNAs-449 downregulation in TNBC and doxorubicin response. MiRNAs-449 are downregulated in TNBC through a negative feedback loop with SIRT1 and HDAC1. Moreover, ACSL4 increases ABCG2 expression, thus diminishing the intracellular doxorubicin concentration and promoting doxorubicin resistance. MiRNAs-449 overexpression downregulates the ACSL4/ABCG2 axis and sensitizes doxorubicin-resistant cells to doxorubicin. Created with BioRender. TNBC: triple-negative breast cancer; DOX: doxorubicin; SIRT1: Sirtuin 1; HDAC1: Histone deacetylase 1; ACSL4: Acyl-CoA Synthetase Long-Chain Family Member 4; ABCG2: ATP-binding cassette superfamily G member 2.© 2024. The Author(s).