About

Gang Lin, Ph.D., is a Professor of Research in Microbiology and Immunology at Weill Cornell Medicine. His research focuses on the discovery and development of novel inhibitors targeting the human 20S proteasome, with the aim of creating new therapies for cancer and immune-related diseases. His lab designs inhibitors with distinct proteasome subunit selectivity, and has discovered that co-inhibition of the β5 and β2 subunits suppresses Nrf1-driven compensatory proteasome synthesis, overcoming a key limitation of current drugs. These covalent yet reversible β5β2 inhibitors demonstrate strong potency in cancer models, including triple-negative breast cancer. Additionally, he advances selective immunoproteasome inhibitors that modulate inflammation while sparing non-immune cells, extending proteasome-targeted therapies beyond multiple myeloma to solid tumors, autoimmune, and inflammatory diseases. Dr. Lin's work also involves the discovery and development of inhibitors and ligands for the novel E3 ligase UBR5, in collaboration with Prof. Ma’s lab. UBR5 is a tumor-promoting E3 ligase frequently dysregulated in breast, ovarian, and prostate cancers, where it drives tumor growth, metastasis, and immune evasion. His research focuses on developing small-molecule inhibitors and UBR5-targeting PROTACs to block or degrade this ligase, and building a UBR5-recruiting PROTAC platform for selective degradation of oncogenic proteins. Furthermore, Dr. Lin is involved in developing next-generation antimalarial Pf20S inhibitors that target the Plasmodium falciparum proteasome, active across multiple parasite life stages, with potential for treatment, prophylaxis, and transmission blocking. His team is also working on oral 'artezomibs' that leverage artemisinin’s mechanism to overcome resistance and prevent its emergence.

Research topics

• Biology
• Immunology
• Biochemistry
• Virology
• Genetics
• Pharmacology

Selected publications

• Intracellular Activation of Dual-Pharmacophore Artezomib Enhances Selective Cytotoxicity in Hematologic Malignancies

  Journal of Medicinal Chemistry · 2026-05-02

  articleOpen accessSenior author

  We describe DQ-9, a dual-pharmacophore artezomib analogue that combines selective inhibition of immunoproteasome β5i with iron-dependent activation of artemisinin. DQ-9 exploits the elevated labile iron pool characteristic of hematologic malignancies, yielding selective cytotoxicity toward leukemia and multiple myeloma cells. DQ-9 affords sustained proteasome inhibition and induces oxidative stress and apoptosis through its iron-mediated activation and subsequent intracellular conversion to additional inhibitory species. In contrast, the deoxy analogue DQ-10, which lacks this activatable component, displays activity attributable solely to β5i inhibition, with correspondingly reduced cytotoxic potency. These findings establish iron-activable, β5i-targeting hybrids as a promising strategy to achieve enhanced selectivity and therapeutic efficacy against hematological malignancies.

  PublisherOA PDFDOI

• The immunoproteasome regulates ILC2 responses by modulating mitochondrial capacity

  Proceedings of the National Academy of Sciences · 2025-11-20 · 2 citations

  articleOpen access

  Type 2 innate lymphoid cells (ILC2s) contribute to type 2 immunity but have also been associated with multiple inflammatory diseases, including airway inflammation and asthma. We report that beyond its function of degrading poly-ubiquitinylated proteins, the immunoproteasome (i-20S) is required for the proper function of ILC2s by controlling their mitochondrial capacity. We found that 90% of the catalytic β subunits of proteasomes in human ILC2s (hILC2s) are the immuno- (β5i) rather than constitutive (β5c) isoform. Specific, noncovalent, reversible inhibition of i-20S β5i (LMP7) in hILC2s induced ROS production, which inhibited aconitase, leading to altered mitochondrial function and reduced levels of ATP. Reprogramming of metabolic status by an LMP7 inhibitor impaired ILC2 activation, without significant cytotoxicity or preventing their recovery. Hence, the selective inhibition of i-20S in ILC2 cells did not kill them but reversibly depleted their ATP, preventing their activation and cytokine secretion. In mice, proteasome inhibition similarly blocked mitochondrial function and ILC2 activation, preventing airway inflammation in response to IL33 and asthma in response to house dust mites. These findings reveal a previously unappreciated linkage between proteasome blockade, central carbon metabolism, and mitochondrial function and identify a strategy to regulate immune cell metabolism in inflammatory diseases.

  PublisherOA PDFDOI

• A recombinant expression system for the <i>Plasmodium falciparum</i> proteasome enables structural analysis of its assembly and the design of selective inhibitors

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-14 · 2 citations

  preprintOpen access

  Abstract The Plasmodium falciparum 20S proteasome (Pf20S) has emerged as a promising antimalarial target. Development of therapeutics to this target has previously relied on native purifications of Pf20S, which is challenging and has limited the scope of previous efforts. Here, we report an effective recombinant Pf20S platform to facilitate drug discovery. Proteasome assembly was carried out in insect cells by co-expressing all fourteen subunits along with the essential chaperone homolog, Ump1. Unexpectedly, the isolated proteins consisted of both a mature and an immature complex. Cryo-EM analysis of the immature complexes revealed structural insights detailing how Ump1 and the propeptides of the β2 and β5 subunits coordinate β-ring assembly, which differ from human and yeast homologs. Biochemical validation confirmed that β1, β2, and β5 subunits of the mature proteasome were catalytically active. Clinical proteasome inhibitors, bortezomib, carfilzomib and marizomib were potent but lacked Pf20S selectivity. However, the tripeptide-epoxyketone J-80 inhibited Pf20S β5 with an IC 50 of 22.4 nM and 90-fold selectivity over human β5. Structural studies using cryo-EM elucidated the basis for the selective binding of J-80. Further evaluation of novel Pf20S-selective inhibitors such as the reversible TDI-8304 and irreversible analogs, 8304-vinyl sulfone and 8304-epoxyketone, confirmed their potency and selectivity over the human constitutive proteasome. This recombinant Pf20S platform facilitates detailed biochemical and structural studies, accelerating the development of selective antimalarial therapeutics.

  PublisherOA PDFDOI

• Case Report: Metastatic lung cancer in Meckel's Cave: a radiotherapy successful case and literature review

  Frontiers in Oncology · 2025-06-19

  articleOpen access

  Background: Meckel's cave (MC) is a highly uncommon site for metastatic disease, particularly from primary lung cancer. Case presentation: We report a clinical case of a 70-year-old man presenting with left trigeminal pain, left ptosis, and restricted abduction of the left eyeball. The patient had a 2-year history of stage IV lung squamous cell carcinoma. Contrast-enhanced brain MRI and FDG-PET/CT showed an ill-defined mass with a heterogeneously enhancing lesion involving the left MC and middle cranial fossa. Stereotactic radiosurgery (SRS, 30 Gy/5 fx) achieved significant improvement in symptoms and regression of radiologic tumors within 1 month. Our review of relevant literature identified only two reported cases of lung adenocarcinoma metastasizing to MC. In addition, we examined the limited literature on other malignant tumors metastatic to MC managed with radiotherapy. Conclusion: This is the first reported case of MC metastasis from lung squamous cell carcinoma successfully treated with SRS. Effective management of MC metastasis requires histology-specific radiotherapy strategies, with squamous cell carcinoma benefiting from hypofractionated SRS.

  PublisherOA PDFDOI

• Exploring the regulatory mechanism of CCNA2 in colorectal cancer: Insights from multiomics and experimental analysis

  Journal of Biological Chemistry · 2025-05-08 · 3 citations

  articleOpen access

  Colorectal cancer (CRC) is the third-most common cancer and the second leading of cancer-related deaths worldwide. The underlying regulatory mechanism of cyclin A2 (CCNA2) in CRC was explored through multiomics and experimental analyses, thus facilitating diagnosis, therapy, and prognosis. GSE9348 and GSE110223 were extracted from Gene Expression Omnibus. Differentially expressed genes (DEGs) were identified via GEO2R. CCNA2, a core gene for CRC, was screened out from the protein-protein interaction network constructed by differentially expressed genes. Its diagnostic, prognostic, and therapeutic value was evaluated in Gene Expression Omnibus, The Cancer Genome Atlas, Human Protein Atlas, and Drug-Gene interaction database via transcriptomics, proteomics, and pharmacogenomics. The correlation between CCNA2 and immune infiltration was determined in Tumor Immune Estimation Resource by immunomics. Transcription factor-mRNA and miRNA-mRNA networks for CCNA2 were constructed in miRnet and miRDB via transcriptomics. The role and regulatory mechanism of CCNA2 in CRC were investigated both in vitro and in vivo. CCNA2 showed excellent diagnostic, therapeutic, and prognostic value in CRC. CCNA2 was closely associated with tumor-infiltrating immunocytes, transcription factors, and miRNAs. The knockdown of CCNA2 inhibited the proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), while inducing apoptosis of CRC cells. CCNA2 acted as a target of miR-548x-3p in regulating the biological behavior of CRC cells via the EMT-signaling pathway. CCNA2 is a potential biomarker for the diagnosis, treatment, and prognosis of CRC. The miR-548x-3p-CCNA2 axis plays a pivotal role in regulating the tumorigenesis of CRC through the EMT-signaling pathway.

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• Association Between the Dietary Index for Gut Microbiota and Frailty: Mediating Role of Body Mass Index

  Food Science & Nutrition · 2025-07-01

  articleOpen access

  ABSTRACT Dietary composition and quality have been linked to the onset of frailty. Although the recently developed Dietary Index for Gut Microbiota (DI‐GM) offers a means to evaluate diet quality based on its impact on the gut microbiota, its relevance to frailty has yet to be determined. This cross‐sectional study utilized data from the NHANES collected between 2007 and 2020. DI‐GM scores were determined based on 14 dietary components, with higher scores indicating a diet more supportive of gut microbiota health. Frailty was evaluated using a validated 49‐item frailty index, with frailty defined as a score of 0.21 or higher. Weighted logistic regression, restricted cubic spline models, and mediation analyses were employed to examine the relationship between DI‐GM scores and frailty. A total of 27,026 eligible participants were included in the analysis. Higher DI‐GM scores were significantly associated with a lower risk of frailty. After full adjustment (Model 3), each one‐point increase in the DI‐GM scores corresponded to a 4% reduction in the odds of frailty (OR: 0.96, 95% CI: 0.92–1.00). Compared to the lowest quartile (Q1), individuals in the highest quartile (Q4) demonstrated significantly lower odds of frailty (OR: 0.81, 95% CI: 0.67–0.99). A nonlinear relationship between DI‐GM scores and frailty was identified ( p for nonlinearity = 0.031). Age, sex, education level, and smoking status were found to potentially moderate this association. Mediation analyses further revealed that body mass index (BMI) partially mediated the relationship, accounting for 24.83% of the effect ( p &lt; 0.001). These results indicate that higher DI‐GM scores are linked to a lower risk of frailty, with BMI partially mediating this relationship. Future longitudinal studies are needed to establish causality and further investigate the underlying mechanisms.

  PublisherDOI

• Stage-specific regulation of the <i>Plasmodium falciparum</i> proteasome activity reveals adaptive rewiring in artemisinin resistance

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-11-23

  preprintOpen access

  Abstract The ubiquitin-proteasome system (UPS) is essential for Plasmodium falciparum to maintain protein homeostasis, adapt to proteotoxic stress, and regulate parasite growth and stage transitions. The proteolytic 20S proteasome core is the central component of the UPS, where unfolded protein substrates are degraded into oligopeptides. Mechanisms regulating malaria parasite proteasome activity are poorly understood and have not been thoroughly studied. This knowledge gap is especially critical in the context of artemisinin (ART) resistance, where parasite survival depends on an enhanced stress response, including a greater reliance on the UPS. Here, we profiled proteasome activity and abundance across the parasite intraerythrocytic developmental cycle (IDC) in both ART-sensitive (ART-S) Dd2 and ART-resistant (ART-R) Dd2K13 R539T parasites. We uncovered striking stage-specific regulation: proteasome activity was abundant in the ring stage, decreased in trophozoites, and then peaked in schizonts. Furthermore, ART-R Dd2K13 R539T parasites exhibited higher ring-stage proteasome activity than ART-S Dd2, despite reduced proteasome abundance, suggesting a unique adaptive rewiring of proteasome function. To study proteasome regulation in the parasite, we manipulated proteasome abundance in Dd2 and Dd2K13 R539T by creating a conditional knockdown of PfUMP1, a conserved proteasome maturation factor. PfUMP1 depletion disrupted 20S assembly, decreased proteasome activity, and led to parasite death. These experiments uncovered two key features of proteasome regulation in P. falciparum : (1) the absence of canonical transcriptional regulation of proteasome genes in response to downregulation of proteasome activity, and (2) ART-R parasites exhibit a ring-stage specific increased sensitivity to proteasome downregulation. Together, our findings reveal a previously unrecognized layer of proteasome regulation in malaria parasites and how, as part of their survival adaptations to decreased hemoglobin uptake associated with ART resistance, these parasites alter proteasome function to survive. This work reinforces the therapeutic potential of the proteasome as a stage- and resistance-specific antimalarial target.

  PublisherOA PDFDOI

• Sugar-sweetened beverage consumption predicts metabolic associated fatty liver disease in patients with type 2 diabetes mellitus

  Frontiers in Endocrinology · 2025-10-01 · 1 citations

  articleOpen accessSenior authorCorresponding

  Background: Metabolic associated fatty liver disease (MAFLD) is a leading cause of chronic liver disease worldwide, with heightened prevalence and progression risks in individuals with type 2 diabetes mellitus (T2DM). Emerging evidence suggests dietary factors, particularly sugar-sweetened beverage (SSB) consumption, may exacerbate metabolic dysregulation, yet this relationship remains underexplored in MAFLD populations. Method: We enrolled 3,305 T2DM patients from Taizhou University Hospital, classifying them into MAFLD and non-MAFLD groups via liver ultrasonography. SSB consumption was quantified as weekly intake. Clinical parameters and SSB consumption were analyzed using logistic regression. External validation leveraged NHANES data, focusing on total sugar intake and surrogate markers. Results: MAFLD patients exhibited significantly higher BMI, waist/hip ratios, and SSB consumption than non-MAFLD counterparts (p<0.001). SSB consumption emerged as an independent MAFLD risk factor, with dose-dependent escalation in MAFLD odds. The MAFLD model based on glycometabolism (MMBG), integrating SSB consumption, C-peptide, and glucose, outperformed traditional indices, such as TyG, VAI, and AIP, achieving superior AUC (0.712 vs. 0.631-0.666), enhanced clinical utility and higher Brier scores (p<0.05, respectively). NHANES validation confirmed BMI, central obesity, hyperglycemia, and sugar intake as MAFLD predictors. Conclusion: SSB consumption independently predicts MAFLD risk in T2DM patients, with synergistic effects from dysregulated glycometabolism. The MMBG model, incorporating SSB consumption and glycometabolic parameters, offers a robust tool for early MAFLD risk identification and personalized interventions.

  PublisherOA PDFDOI

• CDK4/6 Inhibition Reverses MEIS2 Suppression of CRL4 ^CRBN to Enhance Immunomodulatory Drug Therapy in Multiple Myeloma

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-15

  preprintOpen access

  Abstract MEIS2 was identified biochemically as a substrate of cereblon (CRBN), a receptor of the CRL4 CRBN E3 ubiquitin ligase required for the anti-myeloma activity of immunomodulatory drugs (IMiD)s and CELMoDs. However, its function in myeloma is unknown. We discovered that MEIS2 is aberrantly expressed in bone marrow myeloma cells (BMMC)s, and that high MEIS2, CDK4 or CDK6 and low CRBN expression predisposes patients to inferior overall survival in IMiD therapy. Inhibition of CDK4/6 (CDK4/6i) reprograms BMMCs for IMiD vulnerability ex vivo that mimics patient’s response to IMiDs. Mechanistically, CDK4/6i both rapidly accelerates the displacement of MEIS2 from CRBN by IMiD and destabilizes the MEIS2 protein while increasing the CRBN protein in cooperation with IMiD and CELMoD. This enhances CRL4 CRBN ubiquitination of IKZF3 and IKZF1 for degradation that exacerbates the loss of IRF4 to relieve IRF7 for induction of the interferon response, culminating in TRAIL-mediated apoptosis. Additionally, MEIS2 promotes BCMA expression and antagonizes repression of BCMA by IMiD and CELMoD for survival of myeloma cells. Thus, CDK4/6i reverses MEIS2 inhibition of CRL4 CRBN in cooperation with IMiD and CELMoD, and mitigates MEIS2-mediated BCMA signaling for survival, suggesting targeting MEIS2 and CDK4/6 as a new strategy to advance immunomodulatory drug therapy in multiple myeloma.

  PublisherOA PDFDOI

• Protocol for analysis of intracellular conversion of artezomib molecules into new proteasome inhibitors in Plasmodium falciparum parasites

  STAR Protocols · 2024-02-15

  articleOpen accessSenior authorCorresponding

  Artezomibs (ATZs), dual-pharmacophore molecules comprising of artemisinin and a parasite proteasome inhibitor, hijack parasite ubiquitin proteasome system to transform into new proteasome inhibitors following the activation of artemisinin by heme. 1 Here, we present a protocol for using a fluorescent activity-based broad-spectrum proteasome inhibitor probe to study intracellular conversion of ATZ molecules into new proteasome inhibitors in malaria parasites. We describe steps for drug treatment and washout, parasite lysis, proteasome labeling, and visualization. For complete details on the use and execution of this protocol, please refer to Zhan et al. 1 • An assay for assessing intracellular artezomib conversion to novel 20S inhibitors • Detailed steps of removing free compound from both media and cells • In-gel fluorescence scanning to visualize 20S active subunit labeling Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics. Artezomibs (ATZs), dual-pharmacophore molecules comprising of artemisinin and a parasite proteasome inhibitor, hijack parasite ubiquitin proteasome system to transform into new proteasome inhibitors following the activation of artemisinin by heme. Here, we present a protocol for using a fluorescent activity-based broad-spectrum proteasome inhibitor probe to study intracellular conversion of ATZ molecules into new proteasome inhibitors in malaria parasites. We describe steps for drug treatment and washout, parasite lysis, proteasome labeling, and visualization.

  PublisherDOI

Recent grants

• Novel Inhibitors of Malaria Proteasome

  NIH · $466k · 2017–2020

• Macrocyclic proteasome inhibitors for treatment of tuberculosis

  NIH · $466k · 2020–2023

• Selective Plasmodium proteasome inhibitors as novel multi-stage antimalarials

  NIH · $5.3M · 2019–2029

Frequent coauthors

• Wenhu Zhan

  Weill Cornell Medicine

  72 shared

• Carl Nathan

  Cornell University

  70 shared

• Hao Zhang

  Institute of Plant Protection

  60 shared

• Laura A. Kirkman

  Weill Cornell Medicine

  49 shared

• Huilin Li

  Hunan Normal University

  23 shared

• Pradeep K. Singh

  Indian Institute of Technology Indore

  22 shared

• Xiuju Jiang

  Cornell University

  21 shared

• Euna Yoo

  Center for Cancer Research

  20 shared