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摘要: 乳腺癌是女性最常见的恶性肿瘤，治疗耐药现象的存在严重影响患者的预后水平，是临床治疗过程中亟待解决的关键问题。角鲨烯环氧化酶（squalene epoxidase, SQLE）作为胆固醇合成通路中的关键限速酶，以癌基因形式异常表达于约67%的乳腺癌组织中，其高表达状态与肿瘤分级、HER2阳性表型及患者不良预后密切相关，尤其在ER+型乳腺癌中，SQLE高表达与内分泌治疗耐药之间存在显著的相关性。SQLE主要通过多种分子机制推动乳腺癌进展及多药耐药的发生，具体包括激活PI3K/AKT信号通路、抑制肿瘤细胞铁死亡过程、重塑肿瘤免疫抑制微环境等。目前研究发现，SQLE抑制剂（如NB-598）及特比萘芬均具有明确的抗肿瘤活性，且二者与靶向治疗或免疫治疗联合应用时，可呈现出协同增效的潜在价值。尽管SQLE已被证实是乳腺癌预后评估及治疗干预的重要潜在靶点，但目前其临床转化应用仍面临诸多挑战，主要包括药物毒性、乳腺癌不同亚型间的疗效差异及缺乏精准的疗效预测标志物等。因此，未来研究需聚焦高选择性SQLE靶向药物研发、联合治疗方案优化及基于SQLE表达的精准患者分层体系建立，为其临床转化应用提供支撑。Abstract: Breast cancer represents the most prevalent malignancy among women. The phenomenon of therapeutic resistance severely compromises patient prognosis, constituting a critical challenge that demands immediate resolution in clinical practice.Squalene epoxidase (SQLE), functioning as the rate-limiting enzyme within the cholesterol biosynthetic pathway, exhibits aberrant oncogenic expression in approximately 67% of breast cancer tissues. Elevated SQLE levels demonstrate significant correlations with advanced tumor grade, HER2-positive phenotypes, and unfavorable patient outcomes. Notably, within estrogen receptor-positive (ER+) breast cancer subtypes, high SQLE expression shows a marked association with endocrine therapy resistance.SQLE drives breast cancer progression and multidrug resistance through multiple molecular mechanisms, specifically including activation of the PI3K/AKT signaling cascade, suppression of tumor cell ferroptosis, and remodeling of the immunosuppressive microenvironment.Current evidence indicates that SQLE inhibitors (such as NB-598) and terbinafine both possess definitive antineoplastic activity. Moreover, when combined with targeted therapies or immunotherapy, these agents demonstrate potential for synergistic efficacy.Although SQLE has been validated as a significant target for prognostic assessment and therapeutic intervention, its clinical translation faces substantial obstacles. These challenges primarily encompass drug toxicity, variable efficacy across breast cancer molecular subtypes, and the lack of precise biomarkers for predicting therapeutic response.Therefore, future investigations should prioritize the development of highly selective SQLE-targeted therapeutics, optimization of combination regimens, and establishment of precision patient stratification systems based on SQLE expression profiles, thereby providing essential support for clinical application.
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Key words:
- SQLE /
- Breast cancer /
- Therapeutic resistance /
- PI3K/AKT pathway /
- Tumor microenvironment /
- Ferroptosis
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图 1 SQLE 调控 ER stress/WIP1/ATM 及 PI3K/AKT 通路介导乳腺癌耐药机制图
Figure 1. Schematic diagram of SQLE-mediated breast cancer resistance via regulation of ER stress/WIP1/ATM and PI3K/AKT pathways
图 2 SQLE 通过经典与旁路胆固醇代谢调控肿瘤代谢重编程及训练免疫的机制示意图
Figure 2. Schematic diagram of SQLE regulating tumor metabolic reprogramming and trained immunity via canonical and alternative cholesterol metabolism
图 3 SQLE 通过 PI3K/AKT 信号轴及肿瘤免疫微环境调控乳腺癌进展机制示意图
A：PI3K/AKT 信号通路调控；B：肿瘤免疫微环境调控（免疫检查点）；C：肿瘤免疫微环境调控（铁死亡逃逸）。
Figure 3. Schematic diagram of SQLE regulating breast cancer progression via PI3K/AKT signaling axis and tumor immune microenvironment
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