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From resistance to sensitivity: the impact of FADD and lncRNA PPFIA1-AS1 on cisplatin treatment in LUSC

Cancer Gene Therapy volume 33, pages 102–115 (2026) Cite this article

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Abstract

Cisplatin resistance remains a significant challenge in treating lung squamous cell carcinoma (LUSC). The role of FADD in this resistance requires further investigation. Our study revealed that FADD is overexpressed in LUSC patients, correlating with lower survival rates. We also discovered that long-term cisplatin-resistant LUSC cell lines (LUSC-CR) had elevated FADD protein levels, and reducing FADD restored their cisplatin sensitivity. At the same time, LUSC-CR cells resisted cisplatin-induced DNA damage and had enhanced DNA repair, linked to P53’s negative regulation of FADD. Additionally, knockdown of the long non-coding RNA (lncRNA) PPFIA1-AS1 can potentiate drug resistance in LUSC cells by decelerating FADD protein turnover and elevating FADD protein levels. In essence, this study elucidated novel mechanisms underlying cisplatin resistance in LUSC, wherein the PPFIA1-AS1/FADD axis regulates DNA damage and repair. Consequently, targeting the PPFIA1-AS1/FADD axis may present a promising avenue for overcoming cisplatin resistance and enhancing the prognosis of LUSC patients.

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Fig. 1: FADD expression was upregulated in cisplatin-resistant LUSC cells and LUSC patients.
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Fig. 2: FADD regulated cisplatin resistance of LUSC cells.
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Fig. 3: FADD regulated the DNA damage response and DNA repair of LUSC cells.
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Fig. 4: FADD regulates the repair of cisplatin induced DNA damage by blocking the LUSC cell cycle in the G1 phase.
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Fig. 5: p53 upregulates FADD to regulate the repair of DNA damage induced by cisplatin.
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Fig. 6: LncRNA PPFIA1-AS1 negatively regulates FADD protein levels in LUSC cells.
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Fig. 7: PPFIA1-AS1 regulates cellular response to cisplatin by maintaining the protein stability of FADD.
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All data generated or analyzed during this study are included in this published article.

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Funding

This study was supported by grants from the Chinese National Natural Sciences Foundation (82573795, 82370816 and 32250016), Natural Science Foundation of Jiangsu Province (BG2024026, BK20243001, BE2023695, BK20230165, BK20231136), and Changzhou Municipal Department of Science and Technology (CE20246001, CJ20235009, CJ20230017), the Fundamental Research Funds for the Central Universities (0208-14380191) and Jiangsu TargetPharma Laboratories Inc., China.

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  1. These authors contributed equally: Xiaoyao Chang, Dangran Li.

Authors and Affiliations

  1. The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, PR China

    Xiaoyao Chang, Dangran Li, Yuanhao Tan, Fangfang Cai, Shuilian Fu, Hongqin Zhuang & Zi-Chun Hua

  2. Changzhou High-Tech Research Institute of Nanjing University and Jiangsu TargetPharma Laboratories Inc., Changzhou, PR China

    Zi-Chun Hua

  3. Faculty of Pharmaceutical Sciences, Xinxiang Medical University, Xinxiang, Henan, China

    Zi-Chun Hua

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  1. Xiaoyao Chang
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Contributions

ZCH, HZ and DL designed the outline of the paper. HZ, XC and YT wrote the manuscript. FC and XC performed most experiments in this study and prepared the Figures. FC, DL and SF performed the experiments with the animals and helped with the western bolt experiments. SF, XC, FC and HZ analyzed data. All authors have read and approved the final version of this manuscript.

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Correspondence to Hongqin Zhuang or Zi-Chun Hua.

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Chang, X., Li, D., Tan, Y. et al. From resistance to sensitivity: the impact of FADD and lncRNA PPFIA1-AS1 on cisplatin treatment in LUSC. Cancer Gene Ther 33, 102–115 (2026). https://doi.org/10.1038/s41417-025-00986-6

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