From Acute Oxidative Defense to Chronic Metabolic Remodeling: Temporal Transcriptomic Reprogramming and Tissue Responses of Nile Tilapia (<em>Oreochromis niloticus</em>) Gills to Hypoxia

(1) Background: Nile tilapia is a cornerstone of global aquaculture, yet hypoxia remains a critical constraint. This study investigates the hypoxia response mechanisms in the gill tissue of a selectively bred Egyptian strain to elucidate the metabolic pathways and genetic regulators governing its tolerance. (2) Methods: We evaluated antioxidant and metabolic enzyme activities alongside gill histology after hypoxia exposure. Furthermore, transcriptome profiling was conducted to identify enriched pathways, with expression patterns validated via qPCR to distinguish between acute and long-term adaptive responses. (3) Results: Hypoxia significantly altered enzyme activities and caused time-dependent gill damage, ranging from mild swelling to severe rupture. Transcriptomics highlighted starch/sucrose metabolism and PPAR signaling. qPCR confirmed that specific genes peak at 6 h for acute responses, while others gradually increase for long-term adaptation. (4) Conclusions: These findings link energy metabolism with immune regulation, revealing the molecular mechanisms underlying hypoxia tolerance. The identified genes offer valuable insights and genetic resources for breeding resilient Nile tilapia.