SPOCK1 acts as a negative regulator of ferroptosis in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related morbidity and mortality worldwide. Therefore, there is an urgent need to discover precise diagnostic markers and novel therapeutic strategies. A genome-wide association study (GWAS) was conducted using the Kunshan Elderly Cohort to identify genetic susceptibility factors underlying NSCLC. GWAS results identified that seven single-nucleotide polymorphisms (SNPs) were associated with NSCLC risk, including SPOCK1 (SPARC/osteonectin, CWCV, and Kazal-like domains proteoglycan (1), which emerged as a key candidate oncogene driving NSCLC progression. High expression of SPOCK1 in NSCLC tissues was associated with poor prognosis. Subsequently, using NSCLC cell lines with shRNA-mediated SPOCK1 knockdown (loss of function) and plasmid-mediated SPOCK1 overexpression (gain of function), we demonstrated that SPOCK1 significantly promotes in vitro NSCLC cell proliferation, migration, invasion, and cell cycle progression. Furthermore, in vivo mouse studies demonstrated that xenografted SPOCK1-knockdown NSCLC cells exhibited significantly reduced tumor growth and metastasis, whereas xenografted SPOCK1-overexpressing NSCLC cells enhanced tumor progression and metastasis. Mechanistically, SPOCK1 activates the JAK2/STAT3 signaling pathway by interacting with integrin alpha5 beta1 (α5β1) and subsequently upregulating SLC3A2 expression. This regulatory cascade promotes glutathione (GSH) biosynthesis and mitigates the accumulation of reactive oxygen species (ROS) and lipid peroxidation LPO), thereby suppressing ferroptosis in the NSCLC cells. Furthermore, Heat Shock Factor 1 (HSF1) is a critical upstream transcriptional regulator of SPOCK1. Notably, SPOCK1 acts as a pivotal mediator of the immunosuppressive microenvironment in the NSCLC tumors by inducing T-cell exhaustion and promoting infiltration of regulatory T cells (Tregs). In summary, SPOCK1 drives NSCLC progression by inhibiting ferroptosis and inducing an immunosuppressive microenvironment. Therefore, SPOCK1 is a promising therapeutic target in NSCLC.