SSBP1 affects lung adenocarcinoma proliferation by regulating ferroptosis through the ERK/NRF2/GPX4 signaling pathway.
Li Fei, Wu Jincheng, Zhou Yangfan, Zhu Xiaolei, Li Yibin, Chen Jingwei, Qiu Kaiming, Cai Weifeng, Lin Zhicai, Geng Guojun, Mi Yanjun
Abstract
BACKGROUND: Lung adenocarcinoma (LUAD) accounts for roughly half of all lung cancer cases and novel therapeutic targets remain scarce. Ferroptosis, an iron-dependent form of regulated cell death, offers a promising strategy to combat therapy resistance. Mitochondrial single-stranded DNA-binding protein 1 (SSBP1) is critical for mitochondrial genome stability, but its role in ferroptosis and LUAD progression remains undefined. METHODS: We analyzed SSBP1 expression and prognostic value in LUAD using public datasets and clinical specimens. In vitro, we used SSBP1 knockdown/overexpression in LUAD cell lines to assess cell viability, ferroptosis markers (Fe2+, Lipid ROS, MDA, rescue experiments), and mitochondrial function. Transcriptomic sequencing, GSEA, and Western blot were employed to identify the underlying pathway. The therapeutic potential of SSBP1 inhibition combined with the ferroptosis inducer RSL3 was validated in vitro and in a xenograft mouse model. RESULTS: High SSBP1 expression is associated with patient prognosis and restrains lipid peroxidation by sustaining ERK-dependent NRF2 nuclear translocation and subsequent HO-1 and GPX4 expression. Loss of SSBP1 impairs this antioxidant signaling axis, leading to increased ferrous ions and lipid ROS within LUAD cells, ultimately sensitized LUAD cells to RSL3, significantly enhancing ferroptosis and inhibiting tumor growth in vivo. Furthermore, mitochondrial damage resulting from ferroptosis in cancer cells exacerbates the mitochondrial apoptosis pathway induced by SSBP1 dysregulation. CONCLUSION: SSBP1, a mitochondrial-localized protein associated with LUAD patient prognosis, promotes LUAD progression by inhibiting ferroptosis through the ERK/NRF2/GPX4 axis.
Key Findings
- High SSBP1 expression is associated with poor prognosis in lung adenocarcinoma and restrains lipid peroxidation by sustaining ERK-dependent NRF2 nuclear translocation and subsequent HO-1 and GPX4 expression.
- Loss of SSBP1 impairs antioxidant signaling, increases ferrous ions and lipid ROS, sensitizing LUAD cells to ferroptosis inducer RSL3 and inhibiting tumor growth in vivo.
- Mitochondrial damage from ferroptosis exacerbates mitochondrial apoptosis pathways induced by SSBP1 dysregulation.
Clinical Significance
Targeting SSBP1 to promote ferroptosis via the ERK/NRF2/GPX4 pathway may offer a novel therapeutic strategy to inhibit lung adenocarcinoma progression and overcome therapy resistance.
Citation
Li Fei, Wu Jincheng, Zhou Yangfanet al.. SSBP1 affects lung adenocarcinoma proliferation by regulating ferroptosis through the ERK/NRF2/GPX4 signaling pathway. Cellular signalling. 2026-Nov-07.