PAHSA protects hematopoietic stem cells from caspase-4/11-mediated pyroptosis and exhaustion

Yan Qian; Qiannv Liu; Yan Zhang; Shuo Wang; Pengyan Xia

doi:10.59717/j.xinn-life.2026.100178

The Innovation Life > 2026 Vol. 4 > No. 2 > 100178

Next Article Previous Article

ARTICLE Open Access

Cite PDF

PAHSA protects hematopoietic stem cells from caspase-4/11-mediated pyroptosis and exhaustion

1.
Beijing Life Science Academy, Beijing 102200, China
2.
Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China
3.
NHC Key Laboratory of Medical Immunology, Peking University, Beijing 100191, China
4.
Key Laboratory of Molecular Immunology, Chinese Academy of Medical Sciences, Beijing 100191, China
5.
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China

More Information

Corresponding authors: qiany@blsa.com.cn (Y.Q.); xiap@pku.edu.cn (P.X.)
Received Date: December 18, 2025

Accepted Date: March 24, 2026

Published Online: March 30, 2026

The Innovation Life 4(2), https://doi.org/10.59717/j.xinn-life.2026.100178 | Cite this article

GRAPHICAL ABSTRACT

GRAPHICAL ABSTRACT

DownLoad: Full size image

PUBLIC SUMMARY

PUBLIC SUMMARY
1. PAHSA protects hematopoietic stem cells (HSCs) from pyroptosis and maintains hematopoietic homeostasis.
  
  PAHSA inhibits LPS delivery into cytosol, blocking non-canonical inflammasome activation.
  
  PAHSA is potential for anti-infection treatment in obese and diabetic patients.

ABSTRACT

ABSTRACT

Hematopoietic stem cells (HSCs) serve as key resources of the blood system and their maintenance in the bone marrow niche is vital for the host survival. Pyroptosis following inflammasome activation is a common event when myeloid cells encounter danger signals. Whether inflammasome activation takes place in HSCs during their maintenance in the bone marrow is still elusive. Here we show that insufficient PAHSA caused by ATGL deficiency leads to increased pyroptosis and exhaustion of HSCs in Pnpla2 knockout mice. PAHSA affects HSC viability in a cell-extrinsic manner. With the help of HMGB1, seral LPS enters HSC cytosol and induces the non-canonical inflammasome activation mediated by the caspase-4/11, leading to HSC pyroptosis and exhaustion. Seral PAHSA binds LPS and hinders LPS binding to HMGB1, thus limiting the intracellular LPS levels in HSCs. PAHSA protects HSCs from LPS-stimulated non-canonical inflammasome activation and pyroptosis in obese mice, providing a promising approach to ameliorate HSC status in obese people in the future.

FullText(HTML)

REFERENCES

[1]	Laurenti E. and Göttgens B. (2018). From haematopoietic stem cells to complex differentiation landscapes. Nature 553:418−426. DOI:10.1038/nature25022 View in Article CrossRef Google Scholar
[2]	Liggett L. A. and Sankaran V. G. (2020). Unraveling hematopoiesis through the lens of genomics. Cell 182:1384−1400. DOI:10.1016/j.cell.2020.08.030 View in Article CrossRef Google Scholar
[3]	Pinho S. and Frenette P. S. (2019). Haematopoietic stem cell activity and interactions with the niche. Nat. Rev. Mol. Cell Biol. 20:303−320. DOI:10.1038/s41580-019-0103-9 View in Article CrossRef Google Scholar
[4]	Wilkinson A. C., Igarashi K. J. and Nakauchi H. (2020). Haematopoietic stem cell self-renewal in vivo and ex vivo. Nat. Rev. Genet. 21:541−554. DOI:10.1038/s41576-020-0241-0 View in Article CrossRef Google Scholar
[5]	Chavakis T., Mitroulis I. and Hajishengallis G. (2019). Hematopoietic progenitor cells as integrative hubs for adaptation to and fine-tuning of inflammation. Nat. Immunol. 20:802−811. DOI:10.1038/s41590-019-0402-5 View in Article CrossRef Google Scholar
[6]	Schultze J. L., Mass E. and Schlitzer A. (2019). Emerging principles in myelopoiesis at homeostasis and during infection and inflammation. Immunity 50:288−301. DOI:10.1016/j.immuni.2019.01.019 View in Article CrossRef Google Scholar
[7]	Wei Q. and Frenette P. S. (2018). Niches for hematopoietic stem cells and their progeny. Immunity 48:632−648. DOI:10.1016/j.immuni.2018.03.024 View in Article CrossRef Google Scholar
[8]	Pietras E. M., Mirantes-Barbeito C., Fong S., et al. (2016). Chronic interleukin-1 exposure drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal. Nat. Cell. Biol. 18:607−618. DOI:10.1038/ncb3346 View in Article CrossRef Google Scholar
[9]	Takizawa H., Fritsch K., Kovtonyuk L. V., et al. (2017). Pathogen-induced TLR4-TRIF innate immune signaling in hematopoietic stem cells promotes proliferation but reduces competitive fitness. Cell Stem Cell 21:225−240.e225. DOI:10.1016/j.stem.2017.06.013 View in Article CrossRef Google Scholar
[10]	Mistry J. J., Hellmich C., Moore J. A., et al. (2021). Free fatty-acid transport via CD36 drives β-oxidation-mediated hematopoietic stem cell response to infection. Nat. Commun. 12:7130. DOI:10.1038/s41467-021-27460-9 View in Article CrossRef Google Scholar
[11]	Ratajczak M. Z. and Kucia M. (2022). Hematopoiesis and innate immunity: An inseparable couple for good and bad times, bound together by an hormetic relationship. Leukemia 36:23−32. DOI:10.1038/s41375-021-01482-0 View in Article CrossRef Google Scholar
[12]	Xia J., Shen L., Liu Y., et al. (2025). Ace2 safeguards embryonic hematopoietic stem and progenitor cell production by restraining Nlrp3-mediated pyroptosis. Proc. Natl. Acad. Sci. USA 122:e2515641122. DOI:10.1073/pnas.2515641122 View in Article CrossRef Google Scholar
[13]	Newton K., Dixit V. M. and Kayagaki N. (2021). Dying cells fan the flames of inflammation. Science 374:1076−1080. DOI:10.1126/science.abi5934 View in Article CrossRef Google Scholar
[14]	Zhu F., Ma J., Li W., et al. (2023). The orphan receptor Nur77 binds cytoplasmic LPS to activate the non-canonical NLRP3 inflammasome. Immunity 56:753−767.e758. DOI:10.1016/j.immuni.2023.03.003 View in Article CrossRef Google Scholar
[15]	Vanaja S. K., Russo A. J., Behl B., et al. (2016). Bacterial outer membrane vesicles mediate cytosolic localization of LPS and caspase-11 activation. Cell 165:1106−1119. DOI:10.1016/j.cell.2016.04.015 View in Article CrossRef Google Scholar
[16]	Qian Y., Liu Q., Cheng X., et al. (2025). A VgrG2b fragment cleaved by caspase-11/4 promotes Pseudomonas aeruginosa infection through suppressing the NLRP3 inflammasome. elife 13:RP99939. DOI:10.7554/eLife.99939 View in Article Google Scholar
[17]	Deng M., Tang Y., Li W., et al. (2018). The endotoxin delivery protein HMGB1 mediates caspase-11-dependent lethality in sepsis. Immunity 49:740−753.e7. DOI:10.1016/j.immuni.2018.08.016 View in Article CrossRef Google Scholar
[18]	Tang Y., Wang X., Li Z., et al. (2021). Heparin prevents caspase-11-dependent septic lethality independent of anticoagulant properties. Immunity 54:454−467.e456. DOI:10.1016/j.immuni.2021.01.007 View in Article CrossRef Google Scholar
[19]	Shi J., Zhao Y., Wang Y., et al. (2014). Inflammatory caspases are innate immune receptors for intracellular LPS. Nature 514:187−192. DOI:10.1038/nature13683 View in Article CrossRef Google Scholar
[20]	Chen Y., Qin X., An Q., et al. (2018). Mesenchymal stromal cells directly promote inflammation by canonical NLRP3 and non-canonical caspase-11 inflammasomes. EBioMedicine 32:31−42. DOI:10.1016/j.ebiom.2018.05.023 View in Article CrossRef Google Scholar
[21]	Brejchova K., Radner F. P. W., Balas L., et al. (2021). Distinct roles of adipose triglyceride lipase and hormone-sensitive lipase in the catabolism of triacylglycerol estolides. Proc. Natl. Acad. Sci. USA 118. DOI:10.1073/pnas.2020999118 View in Article Google Scholar
[22]	Li W., Liu Q., Qian Y., et al. (2024). Adipose triglyceride lipase suppresses noncanonical inflammasome by hydrolyzing LPS. Nat. Chem. Biol. 20:1434−1442. DOI:10.1038/s41589-024-01569-6 View in Article CrossRef Google Scholar
[23]	Patel R., Santoro A., Hofer P., et al. (2022). ATGL is a biosynthetic enzyme for fatty acid esters of hydroxy fatty acids. Nature 606:968−975. DOI:10.1038/s41586-022-04787-x View in Article CrossRef Google Scholar
[24]	Yore M. M., Syed I., Moraes-Vieira P. M., et al. (2014). Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects. Cell 159:318−332. DOI:10.1016/j.cell.2014.09.035 View in Article CrossRef Google Scholar
[25]	Syed I., Lee J., Moraes-Vieira P. M., et al. (2018). Palmitic acid hydroxystearic acids activate GPR40, which is involved in their beneficial effects on glucose homeostasis. Cell Metab. 27:419−427.e414. DOI:10.1016/j.cmet.2018.01.001 View in Article CrossRef Google Scholar
[26]	Yang Q., Vijayakumar A. and Kahn B. B. (2018). Metabolites as regulators of insulin sensitivity and metabolism. Nat. Rev. Mol. Cell Biol. 19:654−672. DOI:10.1038/s41580-018-0044-8 View in Article CrossRef Google Scholar
[27]	Masters S. L., Gerlic M., Metcalf D., et al. (2012). NLRP1 inflammasome activation induces pyroptosis of hematopoietic progenitor cells. Immunity 37:1009−1023. DOI:10.1016/j.immuni.2012.08.027 View in Article CrossRef Google Scholar
[28]	Shi J., Zhao Y., Wang K., et al. (2015). Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526:660−665. DOI:10.1038/nature15514 View in Article CrossRef Google Scholar
[29]	Miao R., Jiang C., Chang W. Y., et al. (2023). Gasdermin D permeabilization of mitochondrial inner and outer membranes accelerates and enhances pyroptosis. Immunity 56:2523−2541.e2528. DOI:10.1016/j.immuni.2023.10.004 View in Article CrossRef Google Scholar
[30]	Hu J. J., Liu X., Xia S., et al. (2020). FDA-approved disulfiram inhibits pyroptosis by blocking gasdermin D pore formation. Nat. Immunol. 21:736−745. DOI:10.1038/s41590-020-0669-6 View in Article CrossRef Google Scholar
[31]	Wang C., Yang T., Xiao J., et al. (2021). NLRP3 inflammasome activation triggers gasdermin D-independent inflammation. Sci. Immunol. 6:eabj3859. DOI:10.1126/sciimmunol.abj3859 View in Article CrossRef Google Scholar
[32]	Mandal P., Feng Y., Lyons J. D., et al. (2018). Caspase-8 collaborates with caspase-11 to drive tissue damage and execution of endotoxic shock. Immunity 49:42−55.e46. DOI:10.1016/j.immuni.2018.06.011 View in Article CrossRef Google Scholar
[33]	Yang X., Cheng X., Tang Y., et al. (2019). Bacterial endotoxin activates the coagulation cascade through gasdermin D-dependent phosphatidylserine exposure. Immunity 51:983−996.e986. DOI:10.1016/j.immuni.2019.11.005 View in Article CrossRef Google Scholar
[34]	Wei C., Jiang W., Wang R., et al. (2024). Brain endothelial GSDMD activation mediates inflammatory BBB breakdown. Nature 629:893−900. DOI:10.1038/s41586-024-07314-2 View in Article CrossRef Google Scholar
[35]	Rathinam V. A. K., Zhao Y. and Shao F. (2019). Innate immunity to intracellular LPS. Nat. Immunol. 20:527−533. DOI:10.1038/s41590-019-0368-3 View in Article CrossRef Google Scholar
[36]	Wang K., Sun Q., Zhong X., et al. (2020). Structural mechanism for GSDMD targeting by autoprocessed caspases in pyroptosis. Cell 180:941−955.e920. DOI:10.1016/j.cell.2020.02.002 View in Article CrossRef Google Scholar
[37]	Kuda O., Brezinova M., Silhavy J., et al. (2018). Nrf2-mediated antioxidant defense and peroxiredoxin 6 are linked to biosynthesis of palmitic acid ester of 9-hydroxystearic acid. Diabetes 67:1190−1199. DOI:10.2337/db17-1087 View in Article CrossRef Google Scholar
[38]	Gong T., Liu L., Jiang W., et al. (2020). DAMP-sensing receptors in sterile inflammation and inflammatory diseases. Nat. Rev. Immunol. 20:95−112. DOI:10.1038/s41577-019-0215-7 View in Article CrossRef Google Scholar
[39]	Wang Y., Luo W., Han J., et al. (2020). MD2 activation by direct AGE interaction drives inflammatory diabetic cardiomyopathy. Nat. Commun. 11:2148. DOI:10.1038/s41467-020-15978-3 View in Article CrossRef Google Scholar
[40]	Ren Y., Cao L., Wang L., et al. (2021). Autophagic secretion of HMGB1 from cancer-associated fibroblasts promotes metastatic potential of non-small cell lung cancer cells via NFκB signaling. Cell Death Dis. 12:858. DOI:10.1038/s41419-021-04150-4 View in Article CrossRef Google Scholar
[41]	Fu Y., Xiang Y., Wang Y., et al. (2023). The STAT1/HMGB1/NF-κB pathway in chronic inflammation and kidney injury after cisplatin exposure. Theranostics 13:2757−2773. DOI:10.7150/thno.81406 View in Article CrossRef Google Scholar
[42]	Barnett K. C., Li S., Liang K., et al. (2023). A 360° view of the inflammasome: Mechanisms of activation, cell death, and diseases. Cell 186:2288−2312. DOI:10.1016/j.cell.2023.04.025 View in Article CrossRef Google Scholar
[43]	Sundaram B., Tweedell R. E., Prasanth Kumar S., et al. (2024). The NLR family of innate immune and cell death sensors. Immunity 57:674−699. DOI:10.1016/j.immuni.2024.03.012 View in Article CrossRef Google Scholar
[44]	Liu Q., Tang Z., Qian Y., et al. (2025). Eukaryotic ADCY7 catalyzes the production of c-di-AMP to activate the NLRP3 inflammasome. Nat. Chem. Biol. 21:1283−1291. DOI:10.1038/s41589-025-01919-y View in Article CrossRef Google Scholar
[45]	Khan N., Downey J., Sanz J., et al. (2020). M.tuberculosis reprograms hematopoietic stem cells to limit myelopoiesis and impair trained immunity. Cell 183:752−770.e722. DOI:10.1016/j.cell.2020.09.062 View in Article CrossRef Google Scholar
[46]	Carnevalli L. S., Scognamiglio R., Cabezas-Wallscheid N., et al. (2014). Improved HSC reconstitution and protection from inflammatory stress and chemotherapy in mice lacking granzyme B. J. Exp. Med. 211:769−779. DOI:10.1084/jem.20131072 View in Article CrossRef Google Scholar
[47]	Vanickova K., Milosevic M., Ribeiro Bas I., et al. (2023). Hematopoietic stem cells undergo a lymphoid to myeloid switch in early stages of emergency granulopoiesis. Embo j 42:e113527. DOI:10.15252/embj.2023113527 View in Article CrossRef Google Scholar
[48]	Ratajczak M. Z., Bujko K., Ciechanowicz A., et al. (2021). SARS-CoV-2 entry receptor ACE2 is expressed on very small CD45(-) precursors of hematopoietic and endothelial cells and in response to virus spike protein activates the Nlrp3 inflammasome. Stem Cell Rev. Rep. 17:266−277. DOI:10.1007/s12015-020-10010-z View in Article CrossRef Google Scholar
[49]	Choi B. S., Daniel N., Houde V. P., et al. (2021). Feeding diversified protein sources exacerbates hepatic insulin resistance via increased gut microbial branched-chain fatty acids and mTORC1 signaling in obese mice. Nat. Commun. 12:3377. DOI:10.1038/s41467-021-23782-w View in Article CrossRef Google Scholar
[50]	Paluchova V., Oseeva M., Brezinova M., et al. (2020). Lipokine 5-PAHSA is regulated by adipose triglyceride lipase and primes adipocytes for De Novo lipogenesis in mice. Diabetes 69:300−312. DOI:10.2337/db19-0494 View in Article CrossRef Google Scholar

Cited by

ABOUT THIS ARTICLE

Cite this article:

Qian Y., Liu Q., Zhang Y., et al. (2026). PAHSA protects hematopoietic stem cells from caspase-4/11-mediated pyroptosis and exhaustion. The Innovation Life 4:100178. https://doi.org/10.59717/j.xinn-life.2026.100178

Qian Y., Liu Q., Zhang Y., et al. (2026). PAHSA protects hematopoietic stem cells from caspase-4/11-mediated pyroptosis and exhaustion. The Innovation Life 4:100178. https://doi.org/10.59717/j.xinn-life.2026.100178

Welcome!

To request copyright permission to republish or share portions of our works, please visit Copyright Clearance Center's (CCC) Marketplace website at marketplace.copyright.com.

PDF

Figures(7)

Supplementary Information

download_supplementary
SI-Extended

Article Metrics

Article views(964) PDF downloads(306)

PAHSA protects hematopoietic stem cells from caspase-4/11-mediated pyroptosis and exhaustion

GRAPHICAL ABSTRACT

PUBLIC SUMMARY

ABSTRACT