Regulated cell-death programs across patient-resolved proximal-tubule states in acute kidney injury: ASPHD1-silencing increases apoptosis and lipid peroxidation
4 affiliations
- 1Department of Nephrology, Jinhua Hospital Affiliated to Zhejiang University, Jinhua, China
- 2Department of Nephrology, Rheumatology and Immunology, Chongqing University Affiliated Renji Hospital (The Fifth People’s Hospital of Chongqing), Chongqing, China
- 3Department of Emergency, The Affiliated Huai’an Hospital of Xuzhou Medical University and The Second People’s Hospital of Huai’an, Huai’an, China
- 4Department of Nephrology, The Affiliated Huai’an No. 1 People’s Hospital, Nanjing Medical University, Huai’an, China
Abstract
Background: Acute kidney injury (AKI) comprises heterogeneous proximal-tubule (PT) states in which regulated cell-death programs may emerge at different stages, complicating the interpretation of tissue markers and their translation to urine.
Methods: Two independent human kidney transcriptomic cohorts were analyzed separately, and candidate genes were required to replicate in direction, adjusted significance, and an effect-size floor defined before candidate qualification. Candidates were localized in a patient-resolved single-nucleus kidney atlas using individual-level composition analysis and patient-state pseudobulk. Gene sets defined before correlation analysis assessed apoptosis, ferroptosis, pyroptotic inflammatory response, and programmed necrotic cell death. Urinary single-cell data examined cellular accessibility and composition, a longitudinal transplant-biopsy cohort constrained temporal interpretation, and ASPHD1 was silenced in commercial RPTEC/TERT1 cells exposed to cisplatin.
Results: Nine genes met the strict cross-cohort replication criterion. ASPHD1 increased in native-kidney and transplant AKI and localized preferentially to the adaptive PT state. Apoptosis-associated transcriptional enrichment extended across adaptive and degenerative states, whereas ferroptosis-associated enrichment was most evident in degenerative PT. Candidate-to-death and death-to-immune correlations did not survive complete-family correction. ASPHD1 was detectable in urinary renal-proxy cells, but the unpaired urinary data and longitudinal transplant cohort did not establish diagnostic or recovery utility. In RPTEC/TERT1 cells, cisplatin induced ASPHD1, whereas ASPHD1-silencing reduced post-injury viability, increased annexin V-positive and cleaved-caspase-3-positive fractions, increased BAX and BBC3 while reducing BCL2, enhanced C11-BODIPY oxidation, reduced GPX4 fluorescence, and shifted SLC7A11, ACSL4, and PTGS2 in a ferroptosis-associated direction. z-VAD-FMK and ferrostatin-1 partially rescued the corresponding phenotypes.
Conclusion: Human AKI PTs show state-dependent enrichment of regulated cell-death-associated transcriptional programs. ASPHD1 is an adaptive-state candidate whose silencing increases apoptotic and ferroptosis-associated vulnerability in a commercial PT injury model.
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BibTeX
@article{wang2026regulated,
title = {{Regulated cell-death programs across patient-resolved proximal-tubule states in acute kidney injury: ASPHD1-silencing increases apoptosis and lipid peroxidation}},
author = {Zhengtong Wang and Qiaoqiao Gui and Hanjing Zhou and Xiaolei Lan and Yuan Liu and Yiyuan Zhang},
journal = {Frontiers in Cell and Developmental Biology},
year = {2026},
month = oct,
doi = {10.3389/fcell.2026.1954743},
url = {https://doi.org/10.3389/fcell.2026.1954743},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Regulated cell-death programs across patient-resolved proximal-tubule states in acute kidney injury: ASPHD1-silencing increases apoptosis and lipid peroxidation
AU - Zhengtong Wang
AU - Qiaoqiao Gui
AU - Hanjing Zhou
AU - Xiaolei Lan
AU - Yuan Liu
AU - Yiyuan Zhang
PY - 2026
DA - 2026/10/22
JO - Frontiers in Cell and Developmental Biology
DO - 10.3389/fcell.2026.1954743
UR - https://doi.org/10.3389/fcell.2026.1954743
AB - Background: Acute kidney injury (AKI) comprises heterogeneous proximal-tubule (PT) states in which regulated cell-death programs may emerge at different stages, complicating the interpretation of tissue markers and their translation to urine. Methods: Two independent human kidney transcriptomic cohorts were analyzed separately, and candidate genes were required to replicate in direction, adjusted significance, and an effect-size floor defined before candidate qualification. Candidates were localized in a patient-resolved single-nucleus kidney atlas using individual-level composition analysis and patient-state pseudobulk. Gene sets defined before correlation analysis assessed apoptosis, ferroptosis, pyroptotic inflammatory response, and programmed necrotic cell death. Urinary single-cell data examined cellular accessibility and composition, a longitudinal transplant-biopsy cohort constrained temporal interpretation, and ASPHD1 was silenced in commercial RPTEC/TERT1 cells exposed to cisplatin. Results: Nine genes met the strict cross-cohort replication criterion. ASPHD1 increased in native-kidney and transplant AKI and localized preferentially to the adaptive PT state. Apoptosis-associated transcriptional enrichment extended across adaptive and degenerative states, whereas ferroptosis-associated enrichment was most evident in degenerative PT. Candidate-to-death and death-to-immune correlations did not survive complete-family correction. ASPHD1 was detectable in urinary renal-proxy cells, but the unpaired urinary data and longitudinal transplant cohort did not establish diagnostic or recovery utility. In RPTEC/TERT1 cells, cisplatin induced ASPHD1, whereas ASPHD1-silencing reduced post-injury viability, increased annexin V-positive and cleaved-caspase-3-positive fractions, increased BAX and BBC3 while reducing BCL2, enhanced C11-BODIPY oxidation, reduced GPX4 fluorescence, and shifted SLC7A11, ACSL4, and PTGS2 in a ferroptosis-associated direction. z-VAD-FMK and ferrostatin-1 partially rescued the corresponding phenotypes. Conclusion: Human AKI PTs show state-dependent enrichment of regulated cell-death-associated transcriptional programs. ASPHD1 is an adaptive-state candidate whose silencing increases apoptotic and ferroptosis-associated vulnerability in a commercial PT injury model.
SN - 2296-634X
ER -