Lamperis Sophia M, McMahon Kaylin M, Calvert Andrea E, Rink Jonathan S, Vasan Karthik, Pandkar Madhura R, Crentsil Eliana U, Chalmers Zachary R, McDonald Natalie R, Kosmala Cameron J, Bonini Marcelo G, Matei Daniela, Gordon Leo I, Chandel Navdeep S, Thaxton C Shad
Department of Urology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611.
Simpson Querrey Institute for BioNanotechnology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611.
Proc Natl Acad Sci U S A. 2025 Jun 3;122(22):e2502876122. doi: 10.1073/pnas.2502876122. Epub 2025 May 30.
Ferroptosis is a cell death mechanism distinguished by its dependence on iron-mediated lipid oxidation. Cancer cells highly resistant to conventional therapies often demonstrate lipid metabolic and redox vulnerabilities that sensitize them to cell death by ferroptosis. These include a unique dependency on the lipid antioxidant selenoenzyme, glutathione peroxidase 4 (GPx4), that acts as a ferroptosis inhibitor. Synthetic high-density lipoprotein-like nanoparticle (HDL NP) targets the high-affinity HDL receptor scavenger receptor class B type 1 (SR-B1) and regulates cell and cell membrane lipid metabolism. Recently, we reported that targeting cancer cell SR-B1 with HDL NP depleted cell GPx4, which is accompanied by increased cell membrane lipid peroxidation and cancer cell death. These data suggest that HDL NP may induce ferroptosis. Thus, we conducted an unbiased CRISPR-based positive selection screen and target validation studies in ovarian clear cell carcinoma (OCCC) cell lines to ascertain the mechanism through which HDL NP regulates GPx4 and kills cancer cells. The screen revealed two genes, acyl-CoA synthetase long chain family member 4 (ACSL4) and thioredoxin reductase 1 (TXNRD1), whose loss conferred resistance to HDL NP. Validation of ACSL4 supports that HDL NP induces ferroptosis as the predominant mechanism of cell death, while validation of TXNRD1 revealed that HDL NP reduces cellular selenium and selenoprotein production, most notably, GPx4. Accordingly, we define cancer cell metabolic targets that can be simultaneously actuated by a multifunctional, synthetic HDL NP ligand of SR-B1 to kill cancer cells by ferroptosis.
铁死亡是一种细胞死亡机制，其特点是依赖于铁介导的脂质氧化。对传统疗法高度耐药的癌细胞往往表现出脂质代谢和氧化还原方面的脆弱性，这使它们对铁死亡介导的细胞死亡敏感。这些脆弱性包括对脂质抗氧化硒酶谷胱甘肽过氧化物酶4（GPx4）的独特依赖性，GPx4起到铁死亡抑制剂的作用。合成高密度脂蛋白样纳米颗粒（HDL NP）靶向高亲和力HDL受体B1型清道夫受体（SR-B1）并调节细胞和细胞膜脂质代谢。最近，我们报道用HDL NP靶向癌细胞SR-B1会耗尽细胞内的GPx4，同时伴随着细胞膜脂质过氧化增加和癌细胞死亡。这些数据表明HDL NP可能诱导铁死亡。因此，我们在卵巢透明细胞癌（OCCC）细胞系中进行了基于CRISPR的无偏差正向选择筛选和靶点验证研究，以确定HDL NP调节GPx4并杀死癌细胞的机制。筛选揭示了两个基因，酰基辅酶A合成酶长链家族成员4（ACSL4）和硫氧还蛋白还原酶1（TXNRD1），它们的缺失赋予了对HDL NP的抗性。对ACSL4的验证支持HDL NP诱导铁死亡是细胞死亡的主要机制，而对TXNRD1的验证表明HDL NP会降低细胞内硒和硒蛋白的产生，最显著的是GPx4。因此，我们确定了癌细胞代谢靶点，这些靶点可被SR-B1的多功能合成HDL NP配体同时激活，从而通过铁死亡杀死癌细胞。
