At the crossroads of metabolism, immunity, and aging 

The Xian lab’s long-term goal is to enhance immune therapies by uncovering how mitochondrial stress activates the immune system. We focus on how mitochondria-released danger signals—known as danger-associated molecular patterns (DAMPs)—shape immunity. In particular, we study circulating oxidized mitochondrial DNA (Ox-mtDNA), that rises with aging and correlates with autoimmune, metabolic, and neurodegenerative disorders. By defining these pathways, we aim to translate basic discoveries into new diagnostics and therapies for autoimmunity, aging-related conditions, and cancer.

Our recent work revealed that Ox-mtDNA controls the transition from inflammation to autoimmunity, through direct communication between plasmacytoid dendritic cells (pDCs) and T follicular helper (Tfh) cells (Fig. 1). This finding opens two central questions for our lab (Fig. 2):

1. Do pDCs present self-antigens to activate Tfh cells in autoimmune disease?
2. Are Tfh cells pathogenic in aging and neurodegenerative conditions where circulating Ox-mtDNA is elevated?

To address these questions, we combine human and mouse models with approaches in immunology, molecular genetics, biochemistry, cell biology, and bioinformatics. Through this integrated strategy, we will define the molecular mechanisms of immune pathogenesis and ultimately develop new diagnostic and therapeutic strategies for autoimmunity, neurodegeneration and cancer.

• Arthritis National Research Foundation (#1291101)
  “Activation of Antigen-Presenting Plasmacytoid Dendritic Cells in Autoimmune Disease”

About the PI

I am a biomedical scientist passionate about understanding how cellular stress reprograms the immune system to shape health and disease. Trained in Singapore and at UC San Diego, my research journey has taken me from studying mitochondrial dynamics and mitophagy, to uncovering how Ox-mtDNA fuels inflammation, autoimmunity, and aging. At the VBRI and MCW, I am excited to build a collaborative and inclusive lab where curiosity, innovation, and mentorship drive discoveries that can translate into new therapies.

Join the Xian Lab

The Xian Lab is actively recruiting! Come work with us using cutting-edge immunology, genetics, and bioinformatics, to explore the dialogue between mitochondria and the immune system! Together we will push the boundaries of discovery and inspire new strategies to treat autoimmunity, neurodegeneration, and cancer.

Online version of publications available at Google Scholar Profile

https://scholar.google.com/citations?user=lo7V1zQAAAAJ&hl=en&oi=ao

or at PubMed Link https://pubmed.ncbi.nlm.nih.gov/?term=hongxu+xian&sort=date

1. Xian, H., Watari, K., Ohira, M., Brito, J., Buttice, S., Onyuru, J., Zuniga, E., Hoffman, H. and Karin, M. (2025) Mitochondrial DNA oxidation propagates autoimmunity by enabling plasmacytoid dendritic cells to induce TFH differentiation. Nature Immunology. PMID: 40528028; DOI: 10.1038/s41590-025-02179-7
   
   

   – Highlighted by News & Views (Arditi & Crother, Nature Immunology, 2025).

2. Hu, D., Yang, Q., Xian, H., Wang, M., Zheng, H., Mallilankaraman, K., Yu, V. and Liou, Y.C. (2025) Death-associated protein 3 triggers intrinsic apoptosis via Miro1 upon inducing intracellular calcium changes. MedComm. PMID: 40351389, DOI: 10.1002/mco2.70214
3. Nilsson, AR., Xian, H., Shalapour, S., Cammenga, J., & Karin, M. (2023) IRF1 regulates self-renewal and stress-responsiveness to support hematopoietic stem cell maintenance. Science Advances. PMID: 37889967, DOI: 10.1126/sciadv.adg5391
4. Xian, H., & Karin M. (2023). Oxidized mitochondrial DNA: a protective signal gone awry. Trends in Immunology. PMID: 36739208; DOI: 10.1016/j.it.2023.01.006
5. Xian, H., Watari, K., Sanchez-Lopez, E., Offenberger, J., Onyuru, J., Sampath, H., . . . Karin, M. (2022). Oxidized DNA fragments exit mitochondria via mPTP- and VDAC-dependent channels to activate NLRP3 inflammasome and interferon signaling. Immunity. PMID: 35835107, DOI: 10.1016/j.immuni.2022.06.007.
   
   

   – Selected as Best of Immunity 2022; highlighted by Preview (Lawrence et al, Immunity, 2022).

6. Xian, H., Liu, Y., Rundberg Nilsson, A., Gatchalian, R., Crother, T. R., Tourtellotte, W. G., . . . Karin, M., Sanchez-Lopez, E. (2021). Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation. Immunity, PMID: 34115964, DOI:10.1016/j.immuni.2021.05.004.
7. Xian, H., & Liou, Y. C. (2020). Functions of outer mitochondrial membrane proteins: mediating the crosstalk between mitochondrial dynamics and mitophagy. Cell Death & Differentiation. PMID: 33208889, DOI: 10.1038/s41418-020-00657-z
8. Xian, H., Xiao, L., Yang, Q., Shen, H., & Liou, Y.C. (2019). STX17 dynamically regulated by Fis1 induces mitophagy via hierarchical macroautophagic mechanism. Nature Communications. PMID: 31053718, DOI: 10.1038/s41467-019-10096-1
9. Xian, H., & Liou, Y. C. (2019). Loss of MIEF1/MiD51 confers susceptibility to BAX-mediated cell death and PINK1-PRKN-dependent mitophagy. Autophagy. PMID: 30894073, DOI:10.1080/15548627.2019.1596494
10. Xiao, L., Xian, H., Lee, K. Y., Xiao, B., Wang, H., Yu, F., . . . Liou, Y. C. (2015). Death-associated Protein 3 Regulates Mitochondrial-encoded Protein Synthesis and Mitochondrial Dynamics. J Biol Chem, PMID: 26306039, DOI:10.1074/jbc.M115.673343
11. Xiao, B., Goh, J. Y., Xiao, L., Xian, H., Lim, K. L., & Liou, Y. C. (2017). Reactive oxygen species trigger Parkin/PINK1 pathway-dependent mitophagy by inducing mitochondrial recruitment of Parkin. J Biol Chem, PMID: 28848050, DOI:10.1074/jbc.M117.787739