化疗耐药是骨肉瘤（OS）临床治疗的主要障碍。在本研究中，我们研究了 EF-hand 结构域蛋白 1 (EFHD1) 在 OS 化疗耐药中的作用。我们发现EFHD1的表达与化疗后的临床结果高度相关。我们在 143B 细胞中过表达 EFHD1，发现它增加了药物治疗后细胞对细胞死亡的抵抗力。相反，在 143BR 细胞（源自 143B 细胞的对顺铂不敏感的 OS 细胞系）中敲除 EFHD1 会增加其对治疗的敏感性。从机制上讲，EFHD1与腺嘌呤核苷酸转位酶-3（ANT3）结合并抑制其构象变化，从而抑制线粒体膜通透性转换孔（mPTP）的打开。这种效应可以维持线粒体功能，从而有利于操作系统细胞的存活。 ANT3构象抑制剂羧基白术苷（CATR）可促进mPTP开放，与顺铂联合使用可增强EFHD1过表达细胞的化疗敏感性。 ANT3构象抑制剂bongkrekic Acid (BKA)可以抑制mPTP开放，恢复EFHD1敲低细胞的抵抗力。总之，我们的结果表明 EFHD1-ANT3-mPTP 可能是未来 OS 治疗的一个有前途的靶点。© 2024。作者。

Chemoresistance is the main obstacle in the clinical treatment of osteosarcoma (OS). In this study, we investigated the role of EF-hand domain-containing protein 1 (EFHD1) in OS chemotherapy resistance. We found that the expression of EFHD1 was highly correlated with the clinical outcome after chemotherapy. We overexpressed EFHD1 in 143B cells and found that it increased their resistance to cell death after drug treatment. Conversely, knockdown of EFHD1 in 143BR cells (a cisplatin-less-sensitive OS cell line derived from 143B cells) increased their sensitivity to treatment. Mechanistically, EFHD1 bound to adenine nucleotide translocase-3 (ANT3) and inhibited its conformational change, thereby inhibiting the opening of the mitochondrial membrane permeability transition pore (mPTP). This effect could maintain mitochondrial function, thereby favoring OS cell survival. The ANT3 conformational inhibitor carboxyatractyloside (CATR), which can promote mPTP opening, enhanced the chemosensitivity of EFHD1-overexpressing cells when combined with cisplatin. The ANT3 conformational inhibitor bongkrekic acid (BKA), which can inhibit mPTP opening, restored the resistance of EFHD1 knockdown cells. In conclusion, our results suggest that EFHD1-ANT3-mPTP might be a promising target for OS therapy in the future.© 2024. The Author(s).