Biology subjects

Zhang, W. K.

Publications and source records attributed to Zhang, W. K..

3 recordsLinked to original sources

bioRxiv2026

FXR-mediated recruitment of PPP1CB suppresses SMAD2/3 phosphorylation to mitigate pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease with limited treatment options and poorly understood molecular underpinnings. Dysregulated TGF-{beta}/SMAD signaling is a key driver of fibrotic remodeling, promoting persistent myofibroblast activation and excessive extracellular matrix deposition. Here we identify the Farnesoid X receptor (FXR), a bile acid activated nuclear receptor, as a previously unrecognized suppressor of pulmonary fibrosis. FXR expression is significantly reduced in lung tissues from patients with PF and in myofibroblasts derived from BLM-induced mouse models, correlating inversely with fibrosis severity. Genetic ablation of FXR exacerbates BLM-induced pulmonary fibrosis by promoting fibroblast hyperactivation and dysregulation of the TGF-{beta}/SMAD signaling pathway. Mechanistically, we identify PPP1CB as a previously unrecognized FXR-interacting protein in primary myofibroblasts derived from IPF patients. We further show that FXR both increases chromatin accessibility at the PPP1CB locus and assembles a functional complex with PPP1CB, which in turn promotes SMAD2/3 dephosphorylation and suppresses their nuclear translocation. Notably, the clinical-stage FXR agonist TERN101 exhibits potent therapeutic efficacy in a BLM-induced mouse pulmonary fibrosis model. These findings establish FXR as a critical antifibrotic regulator in lung tissue and suggest that pharmacological activation of FXR may offer a promising therapeutic strategy for IPF.

cell biology↗

bioRxiv2025

Respiratory Airway Secretory Cells act as Immune Sentinels in Human Distal Airways

Pulmonary immunity in the human distal respiratory airways is essential for lung function but remains poorly explored, mainly due to limited physiologically relevant models. Here, we develop distal lung organoids containing respiratory airway secretory (RAS) cells, a recently identified epithelial population unique to the distal airways of humans and large mammals, using human pluripotent stem cells (hPSCs). Lineage tracing identified RAS cells as descendants of SOX9brightNKX2-1bright progenitors. Single-cell transcriptomics elucidated that RAS cells exhibited a distinct immune-competent phenotype with enriched genes associated with viral host entry and pattern recognition receptor signaling. Functionally, RAS cells infected by respiratory syncytial virus (RSV) exhibited enhanced antiviral activity marked by upregulation of interferon-stimulated genes (ISGs) and complement component 3 (C3). In contrast, bacterial flagellin or Pseudomonas aeruginosa (PAO1) triggered a TLR5-driven immune response in RAS cells, inducing complement system activation, a response suppressed by selective TLR5 inhibition. Notably, in chronic obstructive pulmonary disease (COPD), RAS cells displayed dysregulated immune activation, characterized by elevated expression of adaptive immune mediators. Together, our findings identify RAS cells as previously unrecognized sensors and effectors of mucosal immunity in the human distal airways and reveal their roles in viral infection, bacterial stimulation, and chronic inflammatory lung disease, providing potential therapeutic targets for respiratory diseases.

cell biology↗

bioRxiv2024

Discovery of orally bioavailable SARS-CoV-2 papain-like protease inhibitor as a potential treatment for COVID-19

The RNA-dependent RNA polymerase (RdRp), 3C-like protease (3CLpro), and papain-like protease (PLpro) are pivotal components in the viral life cycle of SARS-CoV-2, presenting as promising therapeutic targets. Currently, all FDA-approved antiviral drugs against SARS-CoV-2 are RdRp or 3CLpro inhibitors. However, the mutations causing drug resistance have been observed in RdRp and 3CLpro from SARS-CoV-2, which makes it necessary to develop antivirals with novel mechanisms. Through the application of a structure-based drug design (SBDD) approach, we discovered a series of novel potent non-covalent PLpro inhibitors with remarkable in vitro potency and in vivo PK properties. The co-crystal structures of PLpro with leads revealed that the residues D164 and Q269 around the S2 site are critical for improving the inhibitors potency. The lead compound GZNL-P36 not only inhibited SARS-CoV-2 and its variants at the cellular level with EC50 ranging from 58.2 nM to 306.2 nM, but also inhibited HCoV-NL63 and HCoV-229E with EC50 of 81.6 nM and 2.66 M, respectively. Oral administration of the compound resulted in significantly improved survival and notable reductions in lung viral loads and lesions in SARS- CoV-2 infection mouse model, consistent with RNA-seq data analysis. Our results indicate that PLpro inhibitor is a promising SARS-CoV-2 therapy.

microbiology↗