About

Jen-Tsan Ashley Chi is a professor at Duke University School of Medicine with appointments in multiple departments including Molecular Genetics and Microbiology, Medicine, Cell Biology, Pharmacology and Cancer Biology, Radiation Oncology, and Integrative Immunobiology. He is also a member of the Duke Cancer Institute. His research focuses on molecular genetics, cancer biology, and immunobiology, contributing to the understanding of disease mechanisms and potential therapeutic approaches. Dr. Chi is involved in various educational programs, including the Program in Cell and Molecular Biology and the Third Year University Program in Genetics and Genomics, indicating a strong commitment to training the next generation of scientists and clinicians.

Research topics

• Cell biology
• Biology
• Cancer research
• Biochemistry
• Chemistry
• Genetics

Selected publications

• MESH1 functions as a metazoan PAPS phosphatase to regulate sulfation

  Nature Chemical Biology · 2026-04-10

  articleSenior author
  PublisherDOI

• MicroRNAs in metabolic effects with atypical antipsychotics—a scoping review

  Therapeutic Advances in Psychopharmacology · 2026-03-01

  articleOpen access

  Background: Metabolic side effects associated with atypical antipsychotics represent a major challenge in the clinical management of schizophrenia, contributing to poor treatment adherence and an increased risk of relapse. MicroRNAs (miRNAs) have emerged as promising diagnostic biomarkers for schizophrenia, with growing evidence indicating that their expression is modulated by antipsychotic treatment. Dysregulated miRNAs may not only reflect underlying disease mechanisms but also actively contribute to therapeutic response and the development of metabolic side effects. Objectives: This scoping review critically evaluates the current literature on miRNAs in schizophrenia, focusing on their role in modulating treatment response and antipsychotic-induced metabolic disturbances. Key knowledge gaps are identified to inform future translational research. Eligibility criteria: We included studies involving adults or animal models with psychotic symptoms (with schizophrenia as the primary diagnosis) treated with atypical antipsychotics. Eligible studies reported associations between miRNA expression, metabolic parameters, and clinical outcomes. Sources of evidence: A rapid review was conducted using PubMed to identify relevant articles published up to December 1, 2025 and 16 articles were included for final review. Charting methods: Data charting was performed by one reviewer using a pre-developed and piloted form. The review was reported according to the Preferred Reporting items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR checklist). Results: Atypical antipsychotics, particularly those acting on dopamine and serotonin receptors, were shown to modulate specific dysregulated miRNAs. Several of these miRNAs regulate genes involved in metabolic pathways, such as lipid and glucose metabolism, potentially contributing to the variability in cardiometabolic side effects observed across individuals. Conclusion: Emerging evidence suggests that miRNAs may play a dual role in mediating both therapeutic efficacy and metabolic risk in schizophrenia treatment. However, the underlying mechanisms remain incompletely understood. Robust, large-scale studies are urgently needed to validate miRNAs as clinically actionable biomarkers for guiding personalized antipsychotic therapy. Trial registration: A protocol was not prospectively registered, as the aim of this scoping review was exploratory in nature.

  PublisherDOI

• 2128P Total neoadjuvant chemotherapy plus PD-1 antibody in locally advanced gastric or gastro-esophageal junction adenocarcinoma: A proof-of-concept, phase II trial

  Annals of Oncology · 2025-09-01 · 1 citations

  article
  PublisherDOI

• Targeting the ferroptosis pathway: A novel compound, AZD1390, protects the brain after ischemic stroke

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-25 · 3 citations

  preprintOpen accessSenior authorCorresponding

  Abstract Background Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation. This process has been implicated in various diseases, including ischemic stroke. Ischemic stroke leads to oxidative stress, iron overload, and reactive oxygen species (ROS) accumulation, which collectively may trigger ferroptotic neuronal cell death. However, the regulatory mechanisms of ferroptosis in stroke remain poorly understood. Previous studies have identified ataxia telangiectasia mutated (ATM), a DNA damage kinase, as a critical regulator of ferroptosis. However, the therapeutic potential of this discovery remains unknown. Methods We investigated the effect of ATM inhibitors, including the brain-penetrant AZD1390, on ferroptosis using in vitro, ex vivo , and in vivo models of ischemic stroke. Our analysis included assessments of cell viability, lipid peroxidation, ferroptosis marker expression, and infarct volume. Result ATM inhibitors significantly alleviated ferroptosis-induced cell death in cultured cells and ex vivo murine brain slice cultures. In the oxygen-glucose deprivation (OGD) stroke model, treatment with AZD1390 reduced the expression of ferroptosis markers (xCT and PTGS2) and diminished neuronal cell death in rat and mouse brain slices. Furthermore, in a mouse model of ischemic stroke, AZD1390 decreased infarct volume confirming its therapeutic efficacy in vivo . Conclusions This study identifies ferroptosis as a critical mechanism in ischemic stroke-induced neuronal cell death and highlights ATM inhibition, particularly with AZD1390, as a promising therapeutic candidate for mitigating stroke-associated damage. Targeting ferroptosis may provide a translationally relevant strategy to mitigate neuronal injury and improve clinical outcomes for stroke patients.

  PublisherOA PDFDOI

• Evidence for Functional Regulation of the KLHL3/WNK Pathway by O-GlcNAcylation

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-27

  preprintOpen access

  Abstract The 42-member Kelch-like (KLHL) protein family are adaptors for ubiquitin E3 ligase complexes, governing the stability of a wide range of substrates. KLHL proteins are critical for maintaining proteostasis in a variety of tissues and are mutated in human diseases, including cancer, neurodegeneration, and familial hyperkalemic hypertension. However, the regulation of KLHL proteins remains incompletely understood. Previously, we reported that two KLHL family members, KEAP1 and gigaxonin, are regulated by O-linked β- N -acetylglucosamine (O-GlcNAc), an intracellular form of glycosylation. Interestingly, some ubiquitination targets of KEAP1 and gigaxonin are themselves also O-GlcNAcylated, suggesting that multi-level control by this post-translational modification may influence many KLHL pathways. To test this hypothesis, we examined KLHL3, which ubiquitinates with-no-lysine (WNK) kinases to modulate downstream ion channel activity. Our biochemical and glycoproteomic data demonstrate that human KLHL3 and all four WNK kinases (WNK1-4) are O-GlcNAcylated. Moreover, our results suggest that O-GlcNAcylation affects WNK4 function in both osmolarity control and ferroptosis, with potential implications ranging from blood pressure regulation to neuronal health and survival. This work demonstrates the functional regulation of the KLHL3/WNK axis by O-GlcNAcylation and supports a broader model of O-GlcNAc serving as a general regulator of KLHL signaling and proteostasis.

  PublisherOA PDFDOI

• Optimized Monothiol Thioredoxin Derivative (ORP100S) Protects In Vitro and In Vivo from Radiation and Chemotoxicity Without Promoting Tumor Proliferation

  Advanced Science · 2025-09-11

  articleOpen access

  Abstract Human thioredoxin‐1 (TRX) is a target‐selective disulfide reductase with antioxidant, anti‐inflammatory, and regulatory functions that mitigates cellular stresses in various organ systems, providing a compelling rationale for therapeutic use as a broad‐spectrum cell protectant. However, clinical application of recombinant TRX (rhTRX) is constrained by rapid clearance and proliferative intracellular activity. To overcome these limitations, a rationally designed TRX variant, ORP100S, was engineered for enhanced stability, prolonged extracellular target engagement, and improved protective function, with development of novel single‐turnover insulin reduction and hybrid‐immunocapture LC‐MS assays. ORP100S demonstrates high‐yield expression in E. coli (16 g L −1 ) and exhibits significant in vivo mitigating effects when administered subcutaneously to rodents and non‐human primates exposed to otherwise‐lethal total‐body ionizing radiation. Compared to native TRX, ORP100S displays improved pharmacokinetic and pharmacodynamic properties without promoting murine or human cancer cell proliferation. Additionally, ORP100S protects hematopoietic stem/progenitor cells (HSPCs) from chemotherapy‐induced toxicity in vitro and in vivo synergistically with co‐administered granulocyte‐macrophage colony‐stimulating factor (GM‐CSF). Mechanistic studies revealed that ORP100S modulates the Kruppel‐like factor 4 (KLF4)‐p53 pathway to selectively inhibit ferroptosis in HSPCs but not cancer cells. These findings highlight the potential of ORP100S as a novel therapeutic agent for mitigating acute radiation injury and improving the safety and efficacy of chemotherapy without compromising antitumor activity.

  PublisherOA PDFDOI

• NINJ1 in Cell Death and Ferroptosis: Implications for Tumor Invasion and Metastasis

  Cancers · 2025-02-26 · 2 citations

  reviewOpen accessSenior authorCorresponding

  NINJ1 was initially recognized for its role in nerve regeneration and cellular adhesion. Subsequent studies have uncovered its participation in cancer progression, where NINJ1 regulates critical steps in tumor metastasis, such as cell migration and invasion. More recently, NINJ1 has emerged as a multifunctional protein mediating plasma membrane rupture (PMR) in several lytic cell death processes, including apoptosis, necroptosis, and pyroptosis. However, its role in ferroptosis-an iron-dependent form of lytic cell death characterized by lipid peroxidation-remained unclear until 2024. Ferroptosis is a tumor suppression mechanism that may be particularly relevant to detached and metastatic cancer cells. This review explores the role of NINJ1 in tumor invasion and metastasis, focusing on its regulation of ferroptosis via a non-canonical mechanism distinct from other cell deaths. We discuss the process of ferroptosis and its implications for cancer invasion and metastasis. Furthermore, we review recent studies highlighting the diverse roles of NINJ1 in ferroptosis regulation, including its canonical function in PMR and its non-canonical function of modulating intracellular levels of glutathione (GSH) and coenzyme A (CoA) via interaction with xCT anti-porter. Given that ferroptosis has been associated with tumor suppression, metastasis, the elimination of treatment-resistant cancer cells, and tumor dormancy, NINJ1's modulation of ferroptosis presents a promising therapeutic target for inhibiting metastasis. Understanding the dual role of NINJ1 in promoting or restraining ferroptosis depending on cellular context could open avenues for novel anti-cancer strategies to enhance ferroptotic vulnerability in metastatic tumors.

  PublisherOA PDFDOI

• Target sequence-conditioned design of peptide binders using masked language modeling

  Nature Biotechnology · 2025-08-13 · 28 citations

  articleOpen access

  The computational design of protein-based binders presents unique opportunities to access 'undruggable' targets, but effective binder design often relies on stable three-dimensional structures or structure-influenced latent spaces. Here we introduce PepMLM, a target sequence-conditioned designer of de novo linear peptide binders. Using a masking strategy that positions cognate peptide sequences at the C terminus of target protein sequences, PepMLM finetunes the ESM-2 protein language model to fully reconstruct the binder region, achieving low perplexities matching or improving upon validated peptide-protein sequence pairs. After successful in silico benchmarking with AlphaFold-based docking, we experimentally validate the efficacy of PepMLM through both binding and degradation assays. PepMLM-derived peptides demonstrate sequence-specific binding to cancer and reproductive targets, including NCAM1 and AMHR2, and enable targeted degradation of proteins across diverse disease contexts, from Huntington's disease to live viral infections. Altogether, PepMLM enables the design of candidate binders to any target protein, without requiring structural input, facilitating broad applications in therapeutic development.

  PublisherOA PDFDOI

• Coenzyme A protects against ferroptosis via CoAlation of mitochondrial thioredoxin reductase

  Journal of Clinical Investigation · 2025-07-22 · 6 citations

  articleOpen accessSenior author

  The cystine-xCT transporter/glutathione/GPX4 axis is the canonical pathway protecting cells from ferroptosis. Whereas GPX4-targeting ferroptosis-inducing compounds (FINs) act independently of mitochondria, xCT-targeting FINs require mitochondrial lipid peroxidation, though the mechanism remains unclear. Because cysteine is also a precursor for coenzyme A (CoA) biosynthesis, here, we demonstrated that CoA supplementation selectively prevented ferroptosis triggered by xCT inhibition by regulating the mitochondrial thioredoxin system. Our data showed that CoA regulated the in vitro enzymatic activity of mitochondrial thioredoxin reductase-2 (TXNRD2) by covalently modifying the thiol group of cysteine (CoAlation) on Cys-483. Replacing Cys-483 with alanine on TXNRD2 abolished its enzymatic activity and ability to protect cells against ferroptosis. Targeting xCT to limit cysteine import and, therefore, CoA biosynthesis reduced CoAlation on TXNRD2. Furthermore, the fibroblasts from patients with disrupted CoA metabolism had increased mitochondrial lipid peroxidation. In organotypic brain slice cultures, inhibition of CoA biosynthesis led to an oxidized thioredoxin system, increased mitochondrial lipid peroxidation, and loss of cell viability, which were all rescued by ferrostatin-1. These findings identified CoA-mediated posttranslational modification to regulate the thioredoxin system as an alternative ferroptosis protection pathway with potential clinical relevance for patients with disrupted CoA metabolism.

  PublisherOA PDFDOI

• Evidence for functional regulation of the KLHL3/WNK pathway by O-GlcNAcylation

  Glycobiology · 2025-08-11 · 1 citations

  articleOpen access

  The 42-member Kelch-like (KLHL) protein family are adaptors for ubiquitin E3 ligase complexes, governing the stability of a wide range of substrates. KLHL proteins are critical for maintaining proteostasis in a variety of tissues and are mutated in human diseases, including cancer, neurodegeneration, and familial hyperkalemic hypertension. However, the regulation of KLHL proteins remains incompletely understood. Previously, we reported that two KLHL family members, KEAP1 and gigaxonin, are regulated by O-linked β-N-acetylglucosamine (O-GlcNAc), an intracellular form of glycosylation. Interestingly, some ubiquitination targets of KEAP1 and gigaxonin are themselves also O-GlcNAcylated, suggesting that multi-level control by this post-translational modification may influence many KLHL pathways. To test this hypothesis, we examined KLHL3, which ubiquitinates with-no-lysine (WNK) kinases to modulate downstream ion channel activity. Our biochemical and glycoproteomic data demonstrate that human KLHL3 and all four WNK kinases (WNK1-4) are O-GlcNAcylated. Moreover, our results suggest that O-GlcNAcylation affects WNK4 function in both osmolarity control and ferroptosis, with potential implications ranging from blood pressure regulation to neuronal health and survival. This work demonstrates the functional regulation of the KLHL3/WNK axis by O-GlcNAcylation and supports a broader model of O-GlcNAc serving as a general regulator of KLHL signaling and proteostasis.

  PublisherOA PDFDOI

Recent grants

• Biochemical and functional investigation of the novel enzymatic activities of MESH1

  NIH · $2.0M · 2018–2024

• The regulation dephosphorylated-CoA-capped RNA and innate immunity by MESH1

  NIH · $199k · 2020–2022

• Metabolic regulation of KLHL proteins through O-glycosylation

  NIH · $541k · 2019–2023

• NIH Grant R01CA125618

  NIH · $3.3M · 2018

• Metabolic regulation of KLHL proteins through O-glycosylation

  NIH · $1.6M · 2019–2024

Frequent coauthors

• Stephen J. Freedland

  Durham VA Medical Center

  81 shared

• Po‐Han Chen

  Yale University

  76 shared

• Chao‐Chieh Lin

  70 shared

• Jianli Wu

  Duke University

  57 shared

• Mark W. Dewhirst

  50 shared

• Patrick O. Brown

  Stanford University

  45 shared

• Everardo Macias

  Duke Medical Center

  39 shared

• Chien‐Kuang Cornelia Ding

  39 shared