About

Pengda Liu is an Associate Professor of Biochemistry and Biophysics at the University of North Carolina at Chapel Hill. His research focuses on deciphering the molecular mechanisms underlying aberrant signaling events that contribute to tumorigenesis, particularly those mediated by protein modifications and protein-protein interactions. His lab aims to understand how cell signaling networks, which determine cell fate, become dysregulated in cancer, with the goal of identifying novel drug targets and developing new treatment strategies. Liu's work involves exploring the potential of enzymes and their inhibition, including the development of chemical compounds and antibodies as therapeutic tools, to target cancer-associated signaling modules. He has received numerous honors and awards for his scholarly achievements, including the Yang Family Biomedical Scholars Award, the Phillip and Ruth Hettleman Prizes for Scholarly Achievement, and the National Cancer Institute Pathway to Independence Award, among others. His research contributes to a global understanding of the key molecular events that lead to malignant diseases and how these can be targeted for cancer therapy.

Research topics

• Biology
• Cell biology
• Chemistry
• Artificial Intelligence
• Biochemistry
• Computer Science
• Machine Learning
• Cancer research
• Biophysics
• Bioinformatics
• Immunology
• Computational biology
• Internal medicine
• Medicine

Selected publications

• The E3 ligase β-TRCP1 earmarks OTUD3 for destruction to fine-tune cGAS activation

  Journal of Biological Chemistry · 2026-04-17

  articleOpen accessSenior author

  Activation of cytosolic DNA sensing through cyclic GMP-AMP synthase (cGAS) induces the production of type I interferons and proinflammatory cytokines, which are essential for antiviral and antibacterial responses, inflammation, and immune modulation. While hyperactivation of cGAS leads to autoimmune diseases, its inactivation contributes to immune evasion and resistance to immunotherapies. Therefore, cGAS activity must be tightly regulated. One mechanism involves the deubiquitination and stabilization of cGAS by the deubiquitinase OTUD3; however, the upstream signals and pathophysiological cues governing OTUD3 regulation remain poorly understood. Here, we report that the E3 ubiquitin ligase β-TRCP1 targets OTUD3 for ubiquitination and proteasomal degradation. This recognition is dependent on RSK3-mediated phosphorylation of a conserved "ESG" motif in OTUD3, which serves as a phospho-degron for β-TRCP1 binding. Intriguingly, cytosolic DNA challenge inactivates the β-TRCP1/RSK3 pathway, resulting in OTUD3 stabilization and enhanced cGAS activation, representing a fine-tuning mechanism of innate immune signaling. Notably, this DNA-induced inactivation of RSK3 is independent of canonical Ras/MEK/extracellular signal-regulated kinase signaling and DNA damage-responsive kinases, but dependent on mTORC2 signaling. Collectively, our studies identify β-TRCP1/RSK3 as a previously unrecognized upstream signaling axis that regulates OTUD3 protein stability in response to DNA stress, thereby modulating cGAS-driven innate immune responses. This pathway presents a potential therapeutic target for modulating innate immunity in autoimmune diseases and cancer.

  PublisherOA PDFDOI

• Reactive oxygen species (ROS) in cancer: from mechanism to therapeutic implications

  Signal Transduction and Targeted Therapy · 2026-03-18 · 10 citations

  articleOpen access

  Reactive oxygen species (ROS) act as critical secondary messengers in various intracellular signaling pathways that regulate cellular proliferation, differentiation, and survival under normal physiological conditions. However, dysregulation of redox signaling-driven by genetic mutations, epigenetic alterations, and posttranscriptional or posttranslational modifications-plays a central role in malignant transformation and cancer progression. Cancer cells typically exhibit elevated basal ROS levels due to increased metabolic activity, mitochondrial dysfunction, and oncogene activation. This moderate oxidative stress promotes tumorigenesis by inducing DNA damage, genomic instability, and aberrant activation of proliferative and survival pathways, while also contributing to resistance to conventional therapies. Paradoxically, excessive ROS accumulation can overwhelm antioxidant defenses, triggering oxidative stress-induced programmed cell death (PCD) mechanisms, including apoptosis, autophagy, and ferroptosis. Owing to its dual role-facilitating both tumor progression and suppression-ROS have emerged as compelling yet complex targets in cancer therapy. Therapeutic strategies aimed at modulating ROS homeostasis, such as enhancing ROS production, inhibiting antioxidant systems, or targeting downstream redox-regulated signaling nodes, hold promise for selectively eliminating cancer cells. Furthermore, integrating redox profiling or "redox signatures" into personalized medicine approaches may optimize therapeutic efficacy while minimizing off-target toxicity. In this review, we critically examine the Janus-faced role of ROS in carcinogenesis, dissect the molecular pathways regulated by ROS in tumor biology, and explore current advancements, limitations, and future directions in redox-based anticancer therapeutic approaches.

  PublisherOA PDFDOI

• cGAS Inhibits ALDH2 to Suppress Lipid Droplet Function and Regulate MASLD Progression

  UNC Libraries · 2025-11-05

  articleOpen access

  Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor essential for host defense against microbial infections, but its role beyond innate immunity remains unclear. Here, a non-canonical function of cGAS in regulating aldehyde metabolism and lipid homeostasis is identified. This is demonstrated that cGAS directly binds to and suppresses ALDH2 (aldehyde dehydrogenase 2), a key enzyme in ethanol metabolism and lipid peroxidation. Loss of cGAS activates ALDH2, thereby enhancing ethanol tolerance in mice. Elevated ALDH2 activity upon cGAS loss increases aldehyde conversion into acetyl-CoA, promoting histone acetylation and transcription of lipid synthesis genes, which drives lipid droplet accumulation in cells and in cGas^-/- mouse livers. These lipid droplets confer resistance to ferroptosis but simultaneously induce ER stress, impairing STING (stimulator of interferon genes) activation. Functionally, cGas^-/- mice fed with a modified high-fat diet develop exacerbated metabolic dysfunction-associated steatotic liver disease (MASLD), characterized by excessive lipid droplet accumulation in livers compared to wild-type controls. In human MASLD patient cohorts, increased cGAS but reduced ALDH2 mRNA expression is observed relative to healthy individuals. Together, this findings uncover a previously unrecognized role of cGAS in metabolic regulation, independent of its innate immune function. By suppressing ALDH2, cGAS controls lipid droplet biogenesis and stress responses, with direct implications for MASLD pathogenesis.

  PublisherDOI

• Molecular glue degrader function of SPOP enhances STING-dependent immunotherapy efficacy in melanoma models

  UNC Libraries · 2025-11-06

  articleOpen access

  The E3 ligase SPOP plays a context-dependent role in cancer by targeting specific cellular proteins for degradation, thereby influencing cell behavior. However, its role in tumor immunity remains largely unexplored. In this study, we revealed that SPOP targeted the innate immune sensor STING for degradation in a CK1γ phosphorylation-dependent manner to promote melanoma growth. Stabilization of STING by escaping SPOP-mediated degradation enhanced anti-tumor immunity by increasing IFNβ production and ISG expression. Notably, small-molecule SPOP inhibitors not only blocked STING recognition by SPOP, but also acted as molecular glues, redirecting SPOP to target neo-substrates such as CBX4 for degradation. This CBX4 degradation led to increased DNA damage, which in turn activated STING and amplified innate immune responses. In a xenografted melanoma B16 tumor model, single-cell RNA-seq analysis demonstrated that SPOP inhibition induced the infiltration of immune cells associated with anti-PD1 responses. Consequently, SPOP inhibitors synergized with immune checkpoint blockade to suppress B16 tumor growth in syngeneic murine models and enhanced the efficacy of CD19-CAR-T therapy. Our findings highlight a molecular glue degrader property of SPOP inhibitors, with potential implications for other E3 ligase-targeting small molecules designed to disrupt protein-protein interactions.

  PublisherDOI

• Phosphorylation of UDP-glucose dehydrogenase increases glycosaminoglycan biosynthesis and promotes tumor cell motility, spheroid growth, and therapeutic resistance

  Matrix Biology · 2025-10-17 · 3 citations

  articleOpen access

  • RSK2, p70S6K, and SGK1 phosphorylate UGDH at serine 316 • Phosphomimetic UGDH S316D and phosphodeficient UGDH S316A mutants produce UDP-glucuronate • UGDH S316D elevates hyaluronan and glycan synthesis and impairs glucuronidation • UGDH S316D increases motility, proliferation, spheroid growth, and enzalutamide resistance • Phosphorylation of UGDH S316 is a novel mechanism for reprogramming cell phenotype UDP-glucose 6-dehydrogenase (UGDH) is an essential enzyme that catalyzes the oxidation of UDP-glucose to UDP-glucuronate. UGDH is elevated in multiple cancers, including prostate cancer, and is functionally implicated in castration resistant recurrence. UGDH is composed of three dimeric units that associate stably as a hexamer in cellular conditions. The dynamic reorganization of noncovalent interactions at the dimer contact interfaces is essential for UGDH activity. In this study, we examined the functional relevance of a putative AGC kinase motif located at the dimer-dimer interface. We demonstrated that UGDH is phosphorylated in LNCaP cells, specifically at serine 316, by RSK2, p70S6K, and SGK1. To determine the functional implications of UGDH S316 phosphorylation, we generated and characterized phosphomimetic (S316D) and phosphodeficient (S316A) point mutations. Intrinsic properties of the purified recombinant proteins were only modestly affected by the substitutions. The stable overexpression of UGDH S316D in LNCaP cells significantly increased the rate of N- and O-glycan synthesis, as well as the production of hyaluronan and sulfated glycosaminoglycans, while reducing DHT glucuronidation, resulting in significant increases in growth of tumor spheroids, cell proliferation and motility, and resistance to enzalutamide. In contrast, UGDH S316A expression reduced the production of glycans and glycosaminoglycans, restored DHT glucuronidation, and impaired growth and motility. Overall, our results support UGDH phosphorylation as a point of control for intracellular and cell surface glycan production, thereby regulating cell proliferation, anchorage dependence, motility, and tumor cell therapeutic resistance.

  PublisherDOI

• The Rab18/Ras/ERK/FosB/MMP3 Signaling Pathway Mediates Cell Migration Regulation by 2′3′-cGAMP

  International Journal of Molecular Sciences · 2025-06-16 · 2 citations

  articleOpen accessSenior authorCorresponding

  The unique secondary messenger 2'3'-cGAMP, produced by cGAS in response to cytosolic dsDNA, plays a critical role in activating innate immunity by binding to and activating STING via cell-intrinsic, autocrine, or paracrine mechanisms. Recently, we identified Rab18 as a novel, STING-independent binder of 2'3'-cGAMP. Binding of 2'3'-cGAMP to Rab18 promotes Rab18 activation and induces cell migration. However, the downstream mechanisms by which 2'3'-cGAMP-induced Rab18 activation regulates cell migration remain largely unclear. Herein, using phospho-profiling analysis, we identify MAPK signaling as a key downstream effector of the 2'3'-cGAMP/Rab18 axis that promotes the expression of FosB2 and drives cell migration. Furthermore, we identify MMP3 as a major transcriptional target of FosB2, through which the 2'3'-cGAMP/Rab18/MAPK/FosB2 signaling pathway positively regulates cell migration. Together, our findings provide new mechanistic insights into how 2'3'-cGAMP signaling controls cell migration and suggest the potential of MAPK inhibitors to block 2'3'-cGAMP-induced migratory responses.

  PublisherOA PDFDOI

• OTU deubiquitinases in disease: roles and targeting

  Trends in Molecular Medicine · 2025-06-16 · 2 citations

  reviewOpen accessSenior author
  PublisherOA PDFDOI

• Stable Cas9 expression regulates cell growth by facilitating mTORC2 activation

  Nucleic Acids Research · 2025-09-11

  articleOpen accessSenior author

  Clustered regularly interspaced short palindromic repeats (CRISPR), widely used for gene editing, relies on bacterial endonucleases like Cas9 to study gene functions and develop therapies. However, its potential effects on mammalian cellular behavior remain unclear. Here, we systematically profiled effects of stable Cas9 expression on growth of 32 cell lines spanning 9 cancer types and non-cancerous cells, finding growth alterations in a subset. To investigate mechanisms, we established the SpCas9 interactome in DU145 and MDA-MB-231 cells, both showing Cas9-enhanced growth, and identified ribosomal proteins as the top shared interactors. RNA-seq analysis revealed that Cas9 expression in DU145 cells activated PI3K signaling. Mechanistic studies showed that ribosomal proteins, including RPL26 and RPL23a, bind to Sin1, a core mTORC2 component, leading to mTORC2 activation. Notably, SpCas9 interacts with both RPL26/RPL23a and Sin1, acting as a scaffold to stabilize their association and enhance mTORC2 activation, even in the absence of growth factors. Our study systematically characterizes Cas9's effects on cell growth regulation and uncovers a novel Cas9-ribosome-mTORC2 signaling axis that promotes cell growth. These findings underscore the need to consider unintended cellular effects in CRISPR applications and highlight the importance of engineering safer Cas9 variants for biomedical research and clinical therapies.

  PublisherOA PDFDOI

• Potent and selective SETDB1 covalent negative allosteric modulator reduces methyltransferase activity in cells

  Nature Communications · 2025-02-24 · 6 citations

  articleOpen access

  A promising drug target, SETDB1, is a dual methyl-lysine (Kme) reader and methyltransferase implicated in cancer and neurodegenerative disease progression. To help understand the role of the triple Tudor domain (3TD) of SETDB1, its Kme reader, we first identify a low micromolar potency small molecule ligand, UNC6535, which occupies simultaneously both the TD2 and TD3 reader binding sites. Further optimization leads to the discovery of UNC10013, a covalent 3TD ligand targeting Cys385 of SETDB1. UNC10013 is potent with a kinact/KI of 1.0 × 106 M−1s−1 and demonstrates proteome-wide selectivity. In cells, negative allosteric modulation of SETDB1-mediated Akt methylation occurs after treatment with UNC10013. Therefore, UNC10013 is a potent, selective, and cell-active covalent ligand for the 3TD of SETDB1, demonstrating negative allosteric modulator properties and making it a promising tool to study the biological role of SETDB1 in disease progression. Design of cysteine-targeting analogs of a reversible SETDB1 triple Tudor domain (3TD) ligand, UNC6535, led to UNC10013, a potent covalent ligand with high selectivity. UNC10013 demonstrated allosteric inhibition of SETDB1-mediated Akt methylation in cells, a promising approach to SETDB1 therapeutics.

  PublisherOA PDFDOI

• The Rab18/Ras/ERK/FosB/MMP3 Signaling Pathway Mediates Cell Migration Regulation by 2′3′-cGAMP

  UNC Libraries · 2025-07-02

  articleOpen accessSenior author

  The unique secondary messenger 2′3′-cGAMP, produced by cGAS in response to cytosolic dsDNA, plays a critical role in activating innate immunity by binding to and activating STING via cell-intrinsic, autocrine, or paracrine mechanisms. Recently, we identified Rab18 as a novel, STING-independent binder of 2′3′-cGAMP. Binding of 2′3′-cGAMP to Rab18 promotes Rab18 activation and induces cell migration. However, the downstream mechanisms by which 2′3′-cGAMP-induced Rab18 activation regulates cell migration remain largely unclear. Herein, using phospho-profiling analysis, we identify MAPK signaling as a key downstream effector of the 2′3′-cGAMP/Rab18 axis that promotes the expression of FosB2 and drives cell migration. Furthermore, we identify MMP3 as a major transcriptional target of FosB2, through which the 2′3′-cGAMP/Rab18/MAPK/FosB2 signaling pathway positively regulates cell migration. Together, our findings provide new mechanistic insights into how 2′3′-cGAMP signaling controls cell migration and suggest the potential of MAPK inhibitors to block 2′3′-cGAMP-induced migratory responses.

  PublisherDOI

Recent grants

• NIH Grant K99CA181342

  NIH · $339k · 2016

• NIH Grant R00CA181342

  NIH · $653k · 2019

• Cancer Hijacks Enzyme Substrate Mutations to Facilitate Tumorigenesis

  NIH · $395k · 2022–2025

• Targeting EWS-FLI1 protein stability as therapeutic strategy for Ewing sarcoma

  NIH · $372k · 2019–2021

• Elucidating novel functions of cGAS in breast cancer

  NIH · $1.8M · 2020–2026

Frequent coauthors

• Wenyi Wei

  Beth Israel Deaconess Medical Center

  248 shared

• Hiroyuki Inuzuka

  Beth Israel Deaconess Medical Center

  200 shared

• Zhiwei Wang

  160 shared

• Shavali Shaik

  The University of Texas MD Anderson Cancer Center

  135 shared

• David Bernard

  Université Claude Bernard Lyon 1

  121 shared

• Claudio Franceschi

  N. I. Lobachevsky State University of Nizhny Novgorod

  121 shared

• Therese M. Becker

  Ingham Institute

  121 shared

• Arnaud Augert

  121 shared

Education

• Ph.D in Interdisciplinary Program of Biological Sciences, Biology

  East Carolina University

  2008

• Bachelor of Engineering, Bioengineering

  Hefei University of Technology

  2003

Awards & honors

• Yang Family Biomedical Scholars Award, UNC School of Medicin…
• Phillip and Ruth Hettleman Prizes for Scholarly Achievement,…
• Andrew McDonough B+ Foundation Award, 2022
• American Type Culture Collection (ATCC) Innovation Challenge…
• Department of Defense Kidney Cancer Research Program Idea De…