Upon viral infection, the host undergoes extensive metabolic reprogramming that significantly influences both viral replication and innate immune responses. Viruses hijack host metabolic pathways (e.g., glucose, lipid, and cholesterol metabolism) to support their proliferation and survival. Meanwhile, key innate immune pathways, including type I interferon production, inflammasome activation, inflammatory signaling, and programmed cell death, are tightly regulated by the host’s metabolic state.

The NR family, comprising 48 members, is widely expressed in immune cells and metabolic tissues. As crucial metabolic sensors and immune regulators, NRs dynamically orchestrate the crosstalk between host metabolism and innate immunity. However, the precise mechanisms by which NRs regulate virus-induced metabolic reprogramming and innate immune responses remain poorly understood, especially for the orphan NRs that still lack identified ligands.

This project aims to systematically elucidate the roles of NRs in antiviral defense and metabolic regulation using NR overexpression and knockout strategies, diverse viral infection models, and integrated multi-omics approaches. Additionally, we will assess the therapeutic potential of NR-targeting small molecules in vitro and in vivo, exploring their efficacy in treating viral infections and virus-related metabolic disorders.

NRs are critical regulators of tumor cell survival, proliferation, and metabolism. While the roles of nuclear hormone receptors have been well characterized in hormone-dependent cancers, the broader functions of the NR family and their potential functional redundancy in cancer biology remain underexplored. How NRs contribute to metabolic reprogramming that facilitates tumor immune evasion, particularly in resisting T cell-mediated cytotoxicity, requires further investigation.

Beyond their tumor-intrinsic roles, NRs also modulate antitumor immunity by regulating immune cell differentiation, activation, and function. Given that NR activity is tightly regulated by specific ligands, it is critical to understand how NRs respond to tumor-derived metabolites, inflammatory mediators, and cytokine signals within the tumor microenvironment to uncover their immunomodulatory functions.

This project aims to dissect the mechanisms by which NRs regulate tumor immune evasion and antitumor immune responses, with the goal of identifying novel therapeutic targets to enhance the efficacy of cancer immunotherapy.

3. Nuclear receptors and sex differences in immune responses

Biological sex differences are primarily governed by sex chromosomes, gonadal hormones (estrogens and androgens), and their interactions with the immune system. These factors shape the susceptibility to  autoimmune diseases, malignancies, infectious diseases, and influence vaccine responses. Despite growing evidence, the underlying mechanisms driving these disparities remain incompletely understood. Sex hormones exert their effects through NRs, including classical hormone receptors (e.g., ERα, ERβ, AR, PR) and immune-relevant NRs (e.g., GR, PPARs). NR activity is context-dependent, varying by age, tissue type, and disease state; however, their sex-specific roles in immune cells remain largely unexplored.

This project aims to investigate NR-mediated gene regulation at transcriptional, non-transcriptional, and epigenetic levels, providing mechanistic insights beyond hormone-level studies. A deeper understanding of NR functions, interactions, and pharmacological modulation could inform the development of more effective, sex-specific therapeutic strategies.

Dysregulated transcription factor (TF) activity is implicated in a wide range of diseases, including cancer, autoimmune disorders, and neurodegeneration. Traditional methods for measuring TF activity, such as chromatin immunoprecipitation (ChIP) and transcriptomics, provide only indirect and static views, while computational approaches rely on proxy data and lack sufficient precision.

To overcome these limitations, the lab will utilize the STAR (Synthetic Transcription-factor Activity Responsive) sensor screening platform, which encompasses 57,000 synthetic promoters covering all known TF-binding motifs. This high-throughput, direct, and dynamic measurement of TF activity across diverse biological contexts (Wu et al., Nat Commun, 2019), offering unprecedented resolution to profile TF activity in healthy vs. diseased cells (e.g., normal vs. cancer cells). Leveraging disease-causing TF activity, we will engineer a synthetic “sense-and-respond” system that triggers the expression of immune modulators or therapeutic gene expression in response to disease-specific TF activities (Nissim & Wu et al., Cell, 2017).

This project aims to decode disease-specific transcriptional regulatory networks to deepen our understanding of disease progression and pathogenesis and develop highly precise and effective therapeutic strategies.