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Regulated cell-death programs across patient-resolved proximal-tubule states in acute kidney injury: ASPHD1-silencing increases apoptosis and lipid peroxidation

Year: 2026

Type: article

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.

Source: Frontiers in Cell and Developmental Biology

DOI: 10.3389/fcell.2026.1954743

Authors: Zhengtong Wang, Qiaoqiao Gui, Hanjing Zhou, Xiaolei Lan, Yuan Liu, Yiyuan Zhang