Biology subjects

Shaji, S. K.

Publications and source records attributed to Shaji, S. K..

4 recordsLinked to original sources

bioRxiv2025

Immune cell de novo steroidogenesis regulates inflammation resolution and recovery in acute lung injury

Effective resolution of inflammation following acute lung infection or injury is critical for restoring immune and tissue homeostasis to ensure functional recovery. Prolonged or unresolved inflammation can impair lung repair, promote fibrosis, and contribute to pulmonary dysfunction. While systemic steroid signalling is known to modulate general immune responses, the specific role of immune cell-mediated steroidogenesis in regulating lung inflammation and repair remains unknown. Here, we show that immune cell de novo steroidogenesis is essential for resolving inflammation and promoting recovery in a murine model of acute lung injury. During the resolution phase, steroid-synthesizing immune cells, predominantly basophils, are enriched in the lung. Mice with immune cell-specific ablation of de novo steroidogenesis exhibit exacerbated lung injury, impaired resolution of inflammation, and defective tissue repair. These findings reveal a previously unrecognized immunoregulatory function of immune cell-derived steroids and identify immune cell steroidogenesis as a potential therapeutic target for promoting resolution and recovery in inflammatory lung diseases.

immunology↗

bioRxiv2025

Glucocorticoid receptor and RUNX transcription factors cooperatively drive CD8 T cells dysfunction in human cancer

Glucocorticoids (GCs) are potent modulators of immune responses; however, the mechanisms by which GCs regulate gene expression in human CD8 T cells remain incompletely defined. Here, we delineate how physiological cortisol signalling shapes the transcriptional and chromatin landscapes of primary human CD8 T cells. We identify a substantial cohort of GC-responsive genes that are co-regulated through the cooperative activity of the glucocorticoid receptor (GR) and RUNX transcription factors. Integrative RNA sequencing and ChIP sequencing analyses identified genome-wide cortisol-responsive immunoregulatory genes. Genetic deletion of the GR (encoded by NR3C1) abolished cortisol-induced gene expression changes, confirming GR-dependency. Notably, GR chromatin occupancy in cortisol-treated CD8 T cells was strongly enriched at RUNX transcription factor (TF) motif rather than canonical GC response elements (GREs). Co-immunoprecipitation assays validated a ligand-dependent physical interaction between GR and RUNX and revealed the interacting domains. Single-cell transcriptomic analyses of tumour infiltrating CD8 T cells revealed significant enrichment of cortisol-responsive genes, indicating an active GC signalling (response) within the tumour microenvironment. GR-RUNX dual controlled genes were enriched in tumour-infiltrating CD8 T cells across multiple cancer types, including lung adenocarcinoma, head and neck squamous carcinoma, pancreatic cancer, and breast cancer. We found GR-RUNX co-regulated genes are predominantly expressed in the predysfunctional state of CD8 T cell population of different solid tumours. These results suggest that local cortisol signalling within tumour microenvironments drives CD8 T cell dysfunction through GR-RUNX TF cooperation. Collectively, our findings identify RUNX3 TF as a critical mediator of GR signalling in human CD8 T cells and reveal a novel mechanism by which endogenous GCs influence antitumour immunity, which could be therapeutically targetable.

immunology↗

bioRxiv2025

Drug repurposing reveals Posaconazole as a CYP11A1 inhibitor enhancing anti-tumour immunity

Steroid hormones regulate cell physiology and immune function, with dysregulated steroidogenesis promoting cancer progression by supporting tumour growth and suppressing anti-tumour immunity. Targeting CYP11A1, the first and rate-limiting enzyme in steroid biosynthesis, has shown promise in cancer therapy, but safe and effective inhibitors remain an unmet need. Undertaking in silico structure-based drug repurposing approach, we found Posaconazole as an inhibitor of CYP11A1. The docking pose analysis showed that Posaconazole can form multiple hydrogen bonds and hydrophobic interactions with the key residues at the binding site and the cofactor, stabilising the protein-ligand complex. We validated its inhibition efficiency in cell-based assays. In a mouse model of lung metastasis, we demonstrated that Posaconazole restricts metastatic cancer growth by stimulating anti-tumour immunity. These findings highlight Posaconazoles potential as a research tool to study steroidogenesis and as a candidate for further preclinical and clinical evaluation in pathological conditions associated with local steroid production, such as steroidogenic tumours.

immunology↗

bioRxiv2025

Primitive steroidogenesis in mast cells: A novel regulatory mechanism for mast cell function

Mast cells, ancient immune sentinels, are crucial in immune responses, tissue homeostasis and inflammatory pathologies. This study unveils a previously unknown regulatory mechanism in mast cell biology: de novo steroidogenesis. Through comprehensive multi-omics analysis and functional assays, we demonstrate that mast cells express Cyp11a1 and produce pregnenolone, representing a primitive form of steroidogenesis. This cell-intrinsic steroidogenic pathway is essential for mast cell development, survival, and functional regulation. Genetic abrogation of mast cell steroidogenesis leads to exaggerated inflammatory and anaphylactic responses in vivo. Our integrative approach reveals extensive transcriptional and proteomic remodelling during mast cell regranulation, with steroidogenesis playing a pivotal role in coordinating recovery and tissue repair processes. We uncover significant sexual dimorphism in mast cell proteomes and a global uncoupling of transcriptional and translational programmes. These findings advance our understanding of mast cell physiology and provide a foundation for developing targeted therapies for mast cell-associated pathologies.

immunology↗