FADS2-STING Signaling in Sertoli Cells Orchestrates Collagen Deposition and Germ Cell Necroptosis in Idiopathic Non-Obstructive Azoospermia.

Abstract

Idiopathic non-obstructive azoospermia (iNOA) is a severe form of male infertility with poorly defined etiology. While dysregulated lipid metabolism is a hallmark of spermatogenic failure, the molecular drivers linking lipid remodeling to testicular niche deterioration remain elusive. Here, integrated testicular lipidomics and single-cell transcriptomics reveal a metabolic shift from polyunsaturated fatty acid (PUFA)-enriched toward more saturated phospholipids in iNOA testes, accompanied by a selective downregulation of fatty acid desaturase 2 (FADS2) in Sertoli cells. Mechanistically, we demonstrate that FADS2 deficiency acts as a metabolic trigger for stimulator of interferon genes (STING) signaling, which orchestrates a transcriptional reprogramming in Sertoli cells. This process promotes aberrant collagen metabolic reprogramming and peritubular fibrosis while concurrently sensitizing germ cells to interferon-mediated necroptosis. Importantly, restoring FADS2-dependent metabolites (γ-linolenic acid and docosahexaenoic acid) attenuates STING activation and collagen deposition and partially restores spermatogenesis in vivo. Collectively, these findings define the pathological relevance of Sertoli cell-associated FADS2-PUFA remodeling and STING-associated inflammatory activation in iNOA, supporting PUFA replenishment as a potential strategy to mitigate structural niche pathology and germ-cell vulnerability.

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