About

Junying Yuan is the Elizabeth D. Hay Professor of Cell Biology at Harvard Medical School. Her laboratory focuses on understanding the mechanisms of neurodegeneration, addressing the basic mechanisms of cell death and their implications in neurodegenerative diseases through cellular, genetic, molecular, and chemical biological approaches. Her research has identified the role of the unfolded protein response (UPR) as a cellular stress response to the accumulation of unfolded proteins in the endoplasmic reticulum, which plays an important role in mediating neurodegeneration. Yuan's work includes discovering that caspase-12 is specifically expressed in the endoplasmic reticulum and that its deficiency renders cortical neurons resistant to amyloid beta protein toxicity, revealing a novel ER-specific apoptosis pathway. She developed a high throughput assay for ER stress and identified salubrinal, a small molecule inhibitor of ER stress-induced cell death, which acts by inhibiting GADD34/PP1 phosphatase complex. Additionally, her research identified necrostatin-1 as an inhibitor of necroptosis, a non-apoptotic cell death pathway, which may serve as a backup mechanism when apoptosis fails. Her findings demonstrate that necroptosis is relevant to neurodegeneration and acute neurological injury, such as ischemic brain injury, where Nec-1 reduces damage with an extended treatment window.

Research topics

• Biology
• Cell biology
• Cancer research
• Biochemistry
• Pathology
• Medicine
• Immunology
• Chemistry
• Neuroscience

Selected publications

• St3gal5-mediated sialylation of glyco-CD177 on neutrophils restricts neuroinflammation following CNS injury

  Proceedings of the National Academy of Sciences · 2025-04-17 · 5 citations

  articleOpen accessCorresponding

  Neutrophils are the most abundant circulating leukocyte population that play critical roles in neuroinflammation following central nervous system (CNS) injury. CD177, a glycoprotein on neutrophils, is emerging as an important immune regulator which can fundamentally affect multiple human inflammatory diseases. However, the role and regulatory mechanism of CD177 glycobiology of neutrophils in neuroinflammation remain elusive. Here, we show that CD177 + neutrophils expand significantly and infiltrate the injured brain following CNS injury both in the human and mouse. Using single-cell RNA sequencing and genetic approaches, we find CD177 + neutrophils as an anti-inflammatory subset that is critical for modulating neuroinflammation after CNS injury. We further identify St3gal5, a sialyltransferase (ST), that can mediate the sialylation and cell surface presentation of glyco-CD177 on neutrophils. Glycoproteomics reveal downregulated sialylation levels in St3gal5-deficient neutrophils. Neutrophil-specific depletion of St3gal5 prevents the cell surface presentation of CD177 on brain-infiltrated neutrophils and exacerbates neuroinflammation. Administration of the FDA-approved anticonvulsant valproic acid (VPA), an St3gal5 upregulator, promotes the glycosylation of neutrophils and attenuates neuroinflammation following CNS injury. Our study reveals a glycoimmuno-regulatory effect of neutrophils and suggests VPA as a neutrophil glycobiology targeting approach to combat neuroinflammation following CNS injury.

  PublisherDOI

• Dynamic Window-Driven Quantitative Strategies Optimization via Heterogeneous Ensembles

  2025-05-29

  articleSenior author

  This paper introduces a fresh, window-driven approach to building stock portfolios, emphasizing flexibility and precision in navigating complex financial markets. At its core is a hierarchical meta-ensemble model that powers stock price forecasting by combining multiple predictive models, like LSTM and XGBoost, to capture market trends effectively. Paired with a dynamic time window mechanism, the model adapts to real-time market shifts, enhancing prediction accuracy for prices, directions, and volatility. The portfolio optimization framework builds on these forecasts, using smart strategies like semi-decision learning and Langevin multiplicative weight updates to balance risk and return. Through rigorous testing on Chinese share data from 2021 to 2025, the system proves its edge over traditional methods, delivering strong performance in both prediction accuracy and portfolio returns.

  PublisherDOI

• PARP12-mediated mono-ADP-ribosylation as a checkpoint for necroptosis and apoptosis

  Proceedings of the National Academy of Sciences · 2025-06-09 · 7 citations

  articleOpen accessCorresponding

  Necroptosis and apoptosis are two alternatively regulated cell death pathways. Activation of RIPK1 upon engagement of TNFR1 by TNFα may promote necroptosis by interacting with RIPK3 or apoptosis by activating caspases. RIPK1 is extensively regulated by a variety of dynamic posttranslational modifications which control its kinase activity and formation of downstream complexes to mediate necroptosis and apoptosis. Here, we investigate the functional significance and mechanism by which PARP12, a mono-ADP-ribosyltransferase, interacts with RIPK1 and RIPK3 in cells stimulated by IFNγ and TNFα. We show that PARP12 catalyzes the mono-ADP-ribosylation (MARylation) of RIPK1 in both the intermediate domain and the kinase domain, as well as the MARylation of RIPK3. PARP12 deficiency reduces necroptosis by inhibiting the activation of RIPK1 kinase and its interaction with RIPK3, as well as sensitizes to apoptosis by promoting the binding of RIPK1 with caspase-8. Thus, upon induction by IFNs, PARP12 may function as a cellular checkpoint that controls RIPK1 to promote necroptosis and inhibit apoptosis. Importantly, while PARP12 is a known interferon-stimulated gene (ISG), PARP12 deficiency promotes the expression of a subset of ISGs and confers protection against influenza A virus-induced mortality in mice. Our study demonstrates that PARP12 is an important modulator of cellular antiviral response.

  PublisherDOI

• Cooperation of TRADD- and RIPK1-dependent cell death pathways in maintaining intestinal homeostasis

  Nature Communications · 2025-02-22 · 17 citations

  articleOpen accessSenior author

  Dysfunctional NF-κB signaling is critically involved in inflammatory bowel disease (IBD). We investigated the mechanism by which RIPK1 and TRADD, two key mediators of NF-κB signaling, in mediating intestinal pathology using TAK1 IEC deficient model. We show that phosphorylation of TRADD by TAK1 modulates RIPK1-dependent apoptosis. TRADD and RIPK1 act cooperatively to mediate cell death regulated by TNF and TLR signaling. We demonstrate the pathological evolution from RIPK1-dependent ileitis to RIPK1- and TRADD-co-dependent colitis in TAK1 IEC deficient condition. Combined RIPK1 inhibition and TRADD knockout completely protect against intestinal pathology and lethality in TAK1 IEC KO mice. Furthermore, we identify distinctive microbiota dysbiosis biomarkers for RIPK1-dependent ileitis and TRADD-dependent colitis. These findings reveal the cooperation between RIPK1 and TRADD in mediating cell death and inflammation in IBD with NF-κB deficiency and suggest the possibility of combined inhibition of RIPK1 kinase and TRADD as a new therapeutic strategy for IBD. TAK1 is a key mediator of human inflammatory bowel diseases (IBD) through the NF-kB pathway. Here, the authors show that TAK1 phosphorylates TRADD, which cooperates with RIPK1 to intestinal pathology and inflammation in a mouse model of IBD.

  PublisherOA PDFDOI

• Intercellular propagation of RIPK1/RIPK3 amyloid fibrils

  Proceedings of the National Academy of Sciences · 2025-09-16 · 2 citations

  articleOpen accessCorresponding

  The canonical necrosome formed by receptor-interacting protein kinase 1 (RIPK1) and RIPK3 is a functional amyloid fibril structure critical to intracellularly drive necroptosis. Since necroptosis leads to the release of intracellular content, the fate of RIPK1/RIPK3 fibrils after necroptotic cell death has not been investigated. Here, we tracked RIPK1 and RIPK3 coassemblies and found that these fibrillar aggregates could be released into the culture medium after the membrane rupture in necroptotic cells. Interestingly, these RIPK1/RIPK3 fibrils were capable of infiltrating recipient cells and acting as seeds for the nucleation and formation of the endogenous necrosome. Cryo electron microscopy structural analysis unveiled a distinctive S-shaped conformation common to RHIM fibrils of RIPK1 and RIPK3, which can facilitate the cross-seeding of RIPK3 by RIPK1 or RIPK1/RIPK3 fibrils. Our findings suggest the ability of functional RIPK1/RIPK3 amyloid fibrils in intercellular spreading to induce protein conformation change in recipient cells and provide structural insights into the mechanism of RIPK1 and RIPK3 cross-templating to drive necroptosis.

  PublisherDOI

• BSCL2 Deficiency Cause Male Infertility in mice by Impairing Histone Acetylation during Spermiogenesis

  Research Square · 2025-06-20

  preprintOpen access
  PublisherOA PDFDOI

• PARP5A and RNF146 phase separation restrains RIPK1-dependent necroptosis

  Molecular Cell · 2024-01-24 · 23 citations

  articleOpen access
  PublisherOA PDFDOI

• Defective prelamin A processing promotes unconventional necroptosis driven by nuclear RIPK1

  Nature Cell Biology · 2024-03-27 · 21 citations

  article
  PublisherDOI

• Spermidine mediates acetylhypusination of RIPK1 to suppress diabetes onset and progression

  Nature Cell Biology · 2024-11-07 · 24 citations

  articleSenior author
  PublisherDOI

• Reduction of DHHC5-mediated beclin 1 S-palmitoylation underlies autophagy decline in aging

  Nature Structural & Molecular Biology · 2024-01-04 · 39 citations

  article
  PublisherDOI

Recent grants

• NIH Grant R01GM064703

  NIH · $934k · 2005

• NIH Grant R01CA089434

  NIH · $1.5M · 2006

• NIH Grant DP1OD000580

  NIH · $4.2M · 2012

• Investigating the mechanism of TNFalpha mediated cell death in oligodendrocytes

  NIH · $1.9M · 2013–2018

• Investigating the role and mechanism of RIPK1 in mediating cerebrovascular pathology of AD

  NIH · $466k · 2018–2020

Frequent coauthors

• Bing Shan

  Shanghai Institute of Organic Chemistry

  128 shared

• Ying Li

  Shanghai Medical College of Fudan University

  98 shared

• Daichao Xu

  Shanghai Institute of Organic Chemistry

  93 shared

• Michael A. Moskowitz

  Harvard University

  91 shared

• Hideaki Hara

  Gifu Pharmaceutical University

  88 shared

• L Bergeron

  McGill University

  70 shared

• Jonathan L. Tilly

  Northeastern University

  70 shared

• Gloria I. Perez

  Michigan State University

  69 shared

Labs

• Junying Yuan LabPI

Education

• Ph.D. Neuroscience

  Harvard University