# Lysine attenuates acute lung injury by restoring α-tubulin acetylation and ciliary activity **Authors:** Wenyu Yang, Xiaoxiao Meng, Yong Zhu, Xinrun Ma, Zhuoran Cao, Mengmeng Wang, Wentao Dai, Yiming Tao, Xiangdong Jian, Rui Tian, Zhengfeng Yang, Ruilan Wang PMC · DOI: 10.1038/s41420-026-03025-x · Cell Death Discovery · 2026-03-16 ## TL;DR Lysine helps repair lung damage by restoring cell structure and reducing inflammation in acute lung injury models. ## Contribution Lysine is identified as a metabolic-structural orchestrator that improves epithelial repair through tubulin acetylation and ciliary signaling. ## Key findings - Lysine supplementation improved survival in mice with acute lung injury from 0% to 62.5%. - Lysine restored α-tubulin acetylation and ciliary TRPC1 localization, preventing pathological calcium influx. - Ciliogenesis preferentially occurred in SFTPC+ alveolar epithelial type II cells following lysine treatment. ## Abstract Acute respiratory distress syndrome and pulmonary fibrosis stemming from severe acute lung injury (ALI) continue to incur high mortality due to ineffective pulmonary regeneration. While metabolic reprogramming is known to support alveolar epithelial repair, the specific role of amino acid metabolism remains enigmatic. Through integration of scRNA-seq mining analysis of human ALI samples and targeted plasma metabolomics, we identified that lysine was largely declined in injured pulmonary epithelium, accompanied by a deficiency of mitochondrial metabolism. Lysine supplementation dramatically improved survival (from 0% to 62.5% in mice), attenuated extracellular matrix deposition and alveolitis, and suppressed inflammation in murine and non-human primate ALI models. Mechanistically, lysine replenished acetyl-CoA to restore α-tubulin acetylation for rescuing ciliary TRPC1 localization, which prevented pathological STIM1-TRPC1 complex formation, thereby blocking calcium influx-reduced E-Cadherin/ZO-1 abundance in pulmonary epithelial cells. Notably, ciliogenesis preferentially occurred in SFTPC+ alveolar epithelial type II (AT2) cells; thus, lysine supplementation would promote regenerative activation of AT2 cells. Our work established lysine as a metabolic-structural orchestrator that coordinates acetyl-CoA availability to calcium homeostasis and epithelial repair through tubulin-mediated ciliary signaling. ## Linked entities - **Genes:** SFTPC (surfactant protein C) [NCBI Gene 6440], TRPC1 (transient receptor potential cation channel subfamily C member 1) [NCBI Gene 7220], STIM1 (stromal interaction molecule 1) [NCBI Gene 6786], shg (shotgun) [NCBI Gene 37386], TJP1 (tight junction protein 1) [NCBI Gene 7082] - **Proteins:** LOC126710533 (tubulin alpha chain-like), TRPC1 (transient receptor potential cation channel subfamily C member 1), STIM1 (stromal interaction molecule 1), shg (shotgun), TJP1 (tight junction protein 1) - **Chemicals:** lysine (PubChem CID 866), acetyl-CoA (PubChem CID 444493) - **Diseases:** acute respiratory distress syndrome (MONDO:0006502), pulmonary fibrosis (MONDO:0002771), acute lung injury (MONDO:0006502) - **Species:** Mus musculus (taxon 10090) ## Full-text entities - **Genes:** Myc (Myc proto-oncogene, bHLH transcription factor) [NCBI Gene 17869] {aka Myc2, Niard, Nird, bHLHe39}, TUBA1B (tubulin alpha 1b) [NCBI Gene 10376] {aka K-ALPHA-1}, Arl13b (ADP-ribosylation factor-like 13B) [NCBI Gene 68146] {aka A530097K21Rik, A930014M17Rik, Arl2l1, C530009C10Rik, hnn}, CYP19A1 (cytochrome P450 family 19 subfamily A member 1) [NCBI Gene 1588] {aka ARO, ARO1, CPV1, CYAR, CYP19, CYPXIX}, CDH1 (cadherin 1) [NCBI Gene 999] {aka Arc-1, BCDS1, CD324, CDHE, ECAD, LCAM}, ARL13B (ARF like GTPase 13B) [NCBI Gene 200894] {aka ARL2L1, JBTS8}, TRPC1 (transient receptor potential cation channel subfamily C member 1) [NCBI Gene 7220] {aka HTRP-1, TRP1}, Trpc1 (transient receptor potential cation channel, subfamily C, member 1) [NCBI Gene 22063] {aka Mtrp1, Trp1, Trrp1}, STIM1 (stromal interaction molecule 1) [NCBI Gene 6786] {aka D11S4896E, GOK, IMD10, STRMK, TAM, TAM1}, EPCAM (epithelial cell adhesion molecule) [NCBI Gene 4072] {aka Ber-Ep4, BerEp4, DIAR5, EGP-2, EGP314, EGP40}, GAPDH (glyceraldehyde-3-phosphate dehydrogenase) [NCBI Gene 2597] {aka G3PD, GAPD, HEL-S-162eP}, Tjp1 (tight junction protein 1) [NCBI Gene 21872] {aka ZO1}, Sftpc (surfactant associated protein C) [NCBI Gene 20389] {aka Bricd6, SP-C, SP5, SPC, Sftp-2, Sftp2}, CEBPD (CCAAT enhancer binding protein delta) [NCBI Gene 1052] {aka C/EBP-delta, CELF, CRP3, NF-IL6-beta}, Tgfb1 (transforming growth factor, beta 1) [NCBI Gene 21803] {aka TGF-beta1, TGFbeta1, Tgfb, Tgfb-1}, Acta2 (actin alpha 2, smooth muscle, aorta) [NCBI Gene 11475] {aka 0610041G09Rik, Actvs, SMAalpha, SMalphaA, a-SMA, alphaSMA}, Epcam (epithelial cell adhesion molecule) [NCBI Gene 17075] {aka CD326, EGP, EGP-2, Egp314, Ep-CAM, EpCAM1}, Cdh1 (cadherin 1) [NCBI Gene 12550] {aka ARC-1, E-cad, Ecad, L-CAM, UVO, Um}, ALDH7A1 (aldehyde dehydrogenase 7 family member A1) [NCBI Gene 501] {aka ATQ1, EPD, EPEO4, PDE}, Hopx (HOP homeobox) [NCBI Gene 74318] {aka 1110018K11Rik, 1200015P04Rik, 2300002F06Rik, Cameo, Hdop, Hod}, CRP (C-reactive protein) [NCBI Gene 1401] {aka PTX1}, CDH2 (cadherin 2) [NCBI Gene 1000] {aka ACOGS, ADHD8, ARVD14, CD325, CDHN, CDw325}, ORAI1 (ORAI calcium release-activated calcium modulator 1) [NCBI Gene 84876] {aka CRACM1, IMD9, ORAT1, TAM2, TMEM142A}, Cdh2 (cadherin 2) [NCBI Gene 12558] {aka CDHN, N-CAD, Ncad}, TJP1 (tight junction protein 1) [NCBI Gene 7082] {aka ZO-1}, Vim (vimentin) [NCBI Gene 22352], C-reactive protein [NCBI Gene 102126170], HSD17B6 (hydroxysteroid 17-beta dehydrogenase 6) [NCBI Gene 8630] {aka HSE, RODH, SDR9C6}, SFTPC (surfactant protein C) [NCBI Gene 6440] {aka BRICD6, PSP-C, SFTP2, SMDP2, SP-C}, ACTA1 (actin alpha 1, skeletal muscle) [NCBI Gene 58] {aka ACTA, ASMA, CFTD, CFTD1, CFTDM, CMYO2A}, VIM (vimentin) [NCBI Gene 7431], DHTKD1 (dehydrogenase E1 and transketolase domain containing 1) [NCBI Gene 55526] {aka AAKAD, AMOXAD, CMT2Q, E1a, OADC-E1, OADH-E1} - **Diseases:** inflammation (MESH:D007249), cold sores (MESH:D006560), COVID-19 (MESH:D000086382), PF (MESH:D011658), brain trauma (MESH:D000070642), respiratory failure (MESH:D012131), deficiency of mitochondrial metabolism (MESH:D024821), Influenza A (MESH:D007251), severe acute lung injury (MESH:D045169), poisoning (MESH:D011041), calcium dysregulation (MESH:D002128), fibrosis (MESH:D005355), ALI (MESH:D055371), sepsis (MESH:D018805), herpes simplex (MESH:D006561), alveolar epithelial injury (MESH:D009375), brain ischemia (MESH:D002545), viral infections (MESH:D014777), multiple organ failure (MESH:D009102), ARDS (MESH:D012128), lung (MESH:D008171), impairment of mitochondrial metabolism (MESH:D028361), COPD (MESH:D029424), lung injury (MESH:D055370), damage (MESH:D020263), toxicity (MESH:D064420), critical illness (MESH:D016638), alveolar (MESH:D002282), infections (MESH:D007239), injury (MESH:D014947), fibrotic lesions (MESH:D009059), IPF (MESH:D054990) - **Chemicals:** everolimus (MESH:D000068338), PQ (MESH:D010269), pirfenidone (MESH:C093844), tyrosine (MESH:D014443), glucose (MESH:D005947), BCA (MESH:C047117), water (MESH:D014867), TG (MESH:D019284), carbon dioxide (MESH:D002245), Tween 20 (MESH:D011136), LPS (MESH:D008070), palmitate (MESH:D010168), Acetyl Coenzyme (MESH:D000105), SKF-96365 (MESH:C063159), SA (MESH:D019346), leucine (MESH:D007930), aspirin (MESH:D001241), Amino acid (MESH:D000596), HE (MESH:D006371), lysine acetylsalicylate (MESH:C010395), valine (MESH:D014633), penicillin (MESH:D010406), warfarin (MESH:D014859), creatinine (MESH:D003404), Lysine (MESH:D008239), IONO (MESH:D015759), phosphate (MESH:D010710), paraffin (MESH:D010232), NAD (MESH:D009243), isoleucine (MESH:D007532), beta-estradiol (MESH:D004958), Fura-2 AM (MESH:C049925), Na+ (MESH:D012964), NADP (MESH:D009249), tryptophan (MESH:D014364), HEPES (MESH:D006531), lipid (MESH:D008055), essential amino acids (MESH:D000601), nintedanib (MESH:C530716), TRIZOL (MESH:C411644), K+ (MESH:D011188), ambrisentan (MESH:C467894), macitentan (MESH:C533860), F-12 (MESH:C007782), Cl- (MESH:D002713), Fura-2 (MESH:D016257), paraformaldehyde (MESH:C003043), SDS (MESH:D012967), Hydroxyproline (MESH:D006909), glutamine (MESH:D005973), imatinib (MESH:D000068877), chloride (MESH:D002712), Triton-X-100 (MESH:D017830), threonine (MESH:D013912), fatty acid (MESH:D005227), phenylalanine (MESH:D010649), A602769 (-), hydrocortisone (MESH:D006854), GC (MESH:C057580), Calcium (MESH:D002118) - **Species:** Rattus norvegicus (brown rat, species) [taxon 10116], Homo sapiens (human, species) [taxon 9606], Cercopithecidae (monkey, family) [taxon 9527], Mus musculus (house mouse, species) [taxon 10090] - **Mutations:** lysine for 18, P0013D, AT 2-to-AT, lysine for 3 - **Cell lines:** MLE-12 — Mus musculus (Mouse), Transformed cell line (CVCL_3751), S2 — Drosophila melanogaster (Fruit fly), Spontaneously immortalized cell line (CVCL_Z232), C57BL/6 — Mus musculus (Mouse), Transformed cell line (CVCL_C0MU), A549 — Homo sapiens (Human), Lung adenocarcinoma, Cancer cell line (CVCL_0023) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC13039107/full.md ## Figures 7 figures with captions in the complete paper: https://tomesphere.com/paper/PMC13039107/full.md ## References 9 references — full list in the complete paper: https://tomesphere.com/paper/PMC13039107/full.md --- Source: https://tomesphere.com/paper/PMC13039107