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Phenylalanine primes renal tubular redox vulnerability and calcium oxalate crystal retention through a PPARδ-CPT1A fatty-acid oxidation axis.

Λεπτομέρειες βιβλιογραφικής εγγραφής
Τίτλος: Phenylalanine primes renal tubular redox vulnerability and calcium oxalate crystal retention through a PPARδ-CPT1A fatty-acid oxidation axis.
Συγγραφείς: Li P; Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, 610041, China; Department of Urology, Sir Run-Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310006, China., Ma Y; Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, 610041, China., Li Y; Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, 610041, China., Jian Z; Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, 610041, China., Yang M; Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, 610041, China., Fu Y; Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, 610041, China., Yang D; Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: yangdx@scu.edu.cn., Wang K; Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: wangkj@scu.edu.cn., Zhao M; Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: eyoung0801@163.com.
Πηγή: Redox biology [Redox Biol] 2026 Sep; Vol. 95, pp. 104292. Date of Electronic Publication: 2026 Jul 07.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Elsevier, B.V Country of Publication: Netherlands NLM ID: 101605639 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2213-2317 (Electronic) Linking ISSN: 22132317 NLM ISO Abbreviation: Redox Biol Subsets: MEDLINE
Imprint Name(s): Original Publication: [Amsterdam]: Elsevier, B.V., [2013]-
Ιατρικοί όροι (MeSH): Calcium Oxalate*/metabolism , Calcium Oxalate*/chemistry , Kidney Tubules*/metabolism , Kidney Tubules*/pathology , Phenylalanine*/metabolism , Phenylalanine*/blood , Nephrolithiasis*/metabolism , Nephrolithiasis*/pathology , PPAR delta*/metabolism , Fatty Acids*/metabolism, Animals ; Humans ; Mice ; Oxidation-Reduction ; Cell Line ; Glyoxylates ; Male
Περίληψη: Calcium oxalate (CaOx) nephrolithiasis is usually framed as a physicochemical disorder of urinary supersaturation, yet stable crystal retention also requires a permissive tubular epithelial state. Here, we tested whether circulating phenylalanine (Phe) functions as a systemic priming factor that sensitizes renal tubular epithelium to CaOx crystal retention under lithogenic stress. Targeted amino-acid metabolomics in patients with CaOx stones, two-sample Mendelian randomization, glyoxylate-induced mouse nephrolithiasis, HK-2 cell injury assays, renal transcriptomics, pathway-rescue experiments and a Corydalis yanhusuo polysaccharide (CYPN-1) intervention were integrated in a staged translational design. Plasma Phe was elevated in CaOx stone formers, and genetically predicted Phe was positively associated with kidney stone risk without evidence of reverse causality. Phe loading did not independently generate stones but markedly amplified glyoxylate-induced renal crystal deposition and oxalate-triggered crystal adhesion to tubular epithelial cells. Mechanistically, Phe suppressed a PPARδ-CPT1A fatty acid oxidation program, increased reactive oxygen species and lipid peroxidation, and induced a redox-lipotoxic tubular phenotype. Activation of PPARδ or CPT1A rescued fatty acid oxidation signaling, lowered oxidative injury and reduced crystal burden in vitro and in vivo. CYPN-1 lowered circulating Phe, reshaped Phe-related gut microbial functions, restored tubular PPARδ-CPT1A signaling and attenuated crystal deposition. These data identify Phe as a modifiable metabolic sensitizer of tubular redox vulnerability under lithogenic stress and support CaOx nephrolithiasis as a disease in which luminal crystallization and circulation-facing metabolic injury converge at the renal tubule.
(Copyright © 2026 The Authors. Published by Elsevier B.V. All rights reserved.)
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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Contributed Indexing: Keywords: Calcium oxalate; Gut microbiota; PPARδ; Phenylalanine; Redox lipotoxicity; Renal tubule
Substance Nomenclature: 2612HC57YE (Calcium Oxalate)
47E5O17Y3R (Phenylalanine)
0 (PPAR delta)
0 (Fatty Acids)
0 (Glyoxylates)
JQ39C92HH6 (glyoxylic acid)
SCR Disease Name: Nephrolithiasis, Calcium Oxalate
Entry Date(s): Date Created: 20260710 Date Completed: 20260729 Latest Revision: 20260813
Update Code: 20260814
PubMed Central ID: PMC13377012
DOI: 10.1016/j.redox.2026.104292
PMID: 42431158
Βάση Δεδομένων: MEDLINE
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  Data: Phenylalanine primes renal tubular redox vulnerability and calcium oxalate crystal retention through a PPARδ-CPT1A fatty-acid oxidation axis.
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  Data: <searchLink fieldCode="AU" term="%22Li+P%22">Li P</searchLink>; Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, 610041, China; Department of Urology, Sir Run-Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310006, China.<br /><searchLink fieldCode="AU" term="%22Ma+Y%22">Ma Y</searchLink>; Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, 610041, China.<br /><searchLink fieldCode="AU" term="%22Li+Y%22">Li Y</searchLink>; Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, 610041, China.<br /><searchLink fieldCode="AU" term="%22Jian+Z%22">Jian Z</searchLink>; Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, 610041, China.<br /><searchLink fieldCode="AU" term="%22Yang+M%22">Yang M</searchLink>; Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, 610041, China.<br /><searchLink fieldCode="AU" term="%22Fu+Y%22">Fu Y</searchLink>; Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, 610041, China.<br /><searchLink fieldCode="AU" term="%22Yang+D%22">Yang D</searchLink>; Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: yangdx@scu.edu.cn.<br /><searchLink fieldCode="AU" term="%22Wang+K%22">Wang K</searchLink>; Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: wangkj@scu.edu.cn.<br /><searchLink fieldCode="AU" term="%22Zhao+M%22">Zhao M</searchLink>; Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: eyoung0801@163.com.
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  Data: <i>Publisher: </i><searchLink fieldCode="PB" term="%22Elsevier%2C+B%2EV%22">Elsevier, B.V </searchLink><i>Country of Publication: </i>Netherlands <i>NLM ID: </i>101605639 <i>Publication Model: </i>Print-Electronic <i>Cited Medium: </i>Internet <i>ISSN: </i>2213-2317 (Electronic) <i>Linking ISSN: </i><searchLink fieldCode="IS" term="%2222132317%22">22132317 </searchLink><i>NLM ISO Abbreviation: </i>Redox Biol <i>Subsets: </i>MEDLINE
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  Data: <searchLink fieldCode="MM" term="%22Calcium+Oxalate%22">Calcium Oxalate*</searchLink>/<searchLink fieldCode="MM" term="%22Calcium+Oxalate+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Calcium+Oxalate%22">Calcium Oxalate*</searchLink>/<searchLink fieldCode="MM" term="%22Calcium+Oxalate+chemistry%22">chemistry</searchLink> <br /><searchLink fieldCode="MM" term="%22Kidney+Tubules%22">Kidney Tubules*</searchLink>/<searchLink fieldCode="MM" term="%22Kidney+Tubules+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Kidney+Tubules%22">Kidney Tubules*</searchLink>/<searchLink fieldCode="MM" term="%22Kidney+Tubules+pathology%22">pathology</searchLink> <br /><searchLink fieldCode="MM" term="%22Phenylalanine%22">Phenylalanine*</searchLink>/<searchLink fieldCode="MM" term="%22Phenylalanine+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Phenylalanine%22">Phenylalanine*</searchLink>/<searchLink fieldCode="MM" term="%22Phenylalanine+blood%22">blood</searchLink> <br /><searchLink fieldCode="MM" term="%22Nephrolithiasis%22">Nephrolithiasis*</searchLink>/<searchLink fieldCode="MM" term="%22Nephrolithiasis+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Nephrolithiasis%22">Nephrolithiasis*</searchLink>/<searchLink fieldCode="MM" term="%22Nephrolithiasis+pathology%22">pathology</searchLink> <br /><searchLink fieldCode="MM" term="%22PPAR+delta%22">PPAR delta*</searchLink>/<searchLink fieldCode="MM" term="%22PPAR+delta+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Fatty+Acids%22">Fatty Acids*</searchLink>/<searchLink fieldCode="MM" term="%22Fatty+Acids+metabolism%22">metabolism</searchLink><br /><searchLink fieldCode="MH" term="%22Animals%22">Animals</searchLink> ; <searchLink fieldCode="MH" term="%22Humans%22">Humans</searchLink> ; <searchLink fieldCode="MH" term="%22Mice%22">Mice</searchLink> ; <searchLink fieldCode="MH" term="%22Oxidation-Reduction%22">Oxidation-Reduction</searchLink> ; <searchLink fieldCode="MH" term="%22Cell+Line%22">Cell Line</searchLink> ; <searchLink fieldCode="MH" term="%22Glyoxylates%22">Glyoxylates</searchLink> ; <searchLink fieldCode="MH" term="%22Male%22">Male</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Calcium oxalate (CaOx) nephrolithiasis is usually framed as a physicochemical disorder of urinary supersaturation, yet stable crystal retention also requires a permissive tubular epithelial state. Here, we tested whether circulating phenylalanine (Phe) functions as a systemic priming factor that sensitizes renal tubular epithelium to CaOx crystal retention under lithogenic stress. Targeted amino-acid metabolomics in patients with CaOx stones, two-sample Mendelian randomization, glyoxylate-induced mouse nephrolithiasis, HK-2 cell injury assays, renal transcriptomics, pathway-rescue experiments and a Corydalis yanhusuo polysaccharide (CYPN-1) intervention were integrated in a staged translational design. Plasma Phe was elevated in CaOx stone formers, and genetically predicted Phe was positively associated with kidney stone risk without evidence of reverse causality. Phe loading did not independently generate stones but markedly amplified glyoxylate-induced renal crystal deposition and oxalate-triggered crystal adhesion to tubular epithelial cells. Mechanistically, Phe suppressed a PPARδ-CPT1A fatty acid oxidation program, increased reactive oxygen species and lipid peroxidation, and induced a redox-lipotoxic tubular phenotype. Activation of PPARδ or CPT1A rescued fatty acid oxidation signaling, lowered oxidative injury and reduced crystal burden in vitro and in vivo. CYPN-1 lowered circulating Phe, reshaped Phe-related gut microbial functions, restored tubular PPARδ-CPT1A signaling and attenuated crystal deposition. These data identify Phe as a modifiable metabolic sensitizer of tubular redox vulnerability under lithogenic stress and support CaOx nephrolithiasis as a disease in which luminal crystallization and circulation-facing metabolic injury converge at the renal tubule.<br /> (Copyright © 2026 The Authors. Published by Elsevier B.V. All rights reserved.)
– Name: Abstract
  Label: Competing Interests
  Group: Ab
  Data: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
– Name: Ref
  Label: References
  Group: RefInfo
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– Name: SubjectMinor
  Label: Contributed Indexing
  Group:
  Data: <i>Keywords: </i>Calcium oxalate; Gut microbiota; PPARδ; Phenylalanine; Redox lipotoxicity; Renal tubule
– Name: NumberCAS
  Label: Substance Nomenclature
  Group: ID
  Data: 2612HC57YE (Calcium Oxalate)<br />47E5O17Y3R (Phenylalanine)<br />0 (PPAR delta)<br />0 (Fatty Acids)<br />0 (Glyoxylates)<br />JQ39C92HH6 (glyoxylic acid)
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  Data: Nephrolithiasis, Calcium Oxalate
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  Data: <i>Date Created: </i>20260710 <i>Date Completed: </i>20260729 <i>Latest Revision: </i>20260813
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  Data: 20260814
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  Group: ID
  Data: 10.1016/j.redox.2026.104292
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  Data: 42431158
PLink https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=cmedm&AN=42431158
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        Value: 10.1016/j.redox.2026.104292
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        Text: English
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        StartPage: 104292
    Subjects:
      – SubjectFull: Animals
        Type: general
      – SubjectFull: Humans
        Type: general
      – SubjectFull: Mice
        Type: general
      – SubjectFull: Oxidation-Reduction
        Type: general
      – SubjectFull: Cell Line
        Type: general
      – SubjectFull: Glyoxylates
        Type: general
      – SubjectFull: Male
        Type: general
      – SubjectFull: Calcium Oxalate metabolism
        Type: general
      – SubjectFull: Calcium Oxalate chemistry
        Type: general
      – SubjectFull: Kidney Tubules metabolism
        Type: general
      – SubjectFull: Kidney Tubules pathology
        Type: general
      – SubjectFull: Phenylalanine metabolism
        Type: general
      – SubjectFull: Phenylalanine blood
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      – SubjectFull: Nephrolithiasis metabolism
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      – SubjectFull: Fatty Acids metabolism
        Type: general
    Titles:
      – TitleFull: Phenylalanine primes renal tubular redox vulnerability and calcium oxalate crystal retention through a PPARδ-CPT1A fatty-acid oxidation axis.
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            – D: 01
              M: 09
              Text: 2026 Sep
              Type: published
              Y: 2026
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