Chronic activation of innate immunity in corals exposed to ocean acidification (OA) correlates with poor restoration outcomes, reduced growth, and increased mortality [https://discovery.researcher.life/article/immune-gene-expression-as-a-biomarker-for-predicting-restoration-success-in-the-branching-coral-acropora-cervicornis/2c83c0d73b6735d2899eeca75867b9ea]. This pattern mirrors vertebrate inflammaging, where sustained immune signaling shifts from protective to pathological [https://pmc.ncbi.nlm.nih.gov/articles/PMC12711513/]. We hypothesize that the proximate driver of this shift is NADPH oxidase (NOX)–derived reactive oxygen species (ROS) that simultaneously damage the coral mucus glycocalyx and impair beneficial microbiome members, thereby creating a feedforward loop of immune activation and holobiont decline.

Mechanistically, OA‑induced elevation of pattern‑recognition receptor signaling upregulates NOX complexes in coral hemocytes and epidermal cells. ROS produced by NOX oxidize mucin glycans and cross‑linking proteins, weakening the mucus barrier that normally houses mutualistic Endozoicomonas up to 87 % in resilient holobionts [https://pmc.ncbi.nlm.nih.gov/articles/PMC8105028/]. A compromised mucus layer releases host‑derived damage‑associated molecular patterns (DAMPs) that further stimulate NOX activity, amplifying ROS production. At the same time, ROS and antimicrobial peptides released during immune activation selectively inhibit Endozoicomonas while favoring opportunistic, mucus‑degrading Vibrio spp., destabilizing the microbiome and accelerating tissue loss.

If NOX‑derived ROS are the mechanistic link between environmental stress and immunity‑driven aging, then pharmacological inhibition of NOX should preserve mucus integrity, maintain a healthy microbiome, and improve holobiont fitness under OA, independent of broader antioxidant defenses.

Testable prediction: Fragments of Acropora cervicornis maintained under elevated pCO₂ (OA conditions) will show (1) higher NOX transcript and enzymatic activity, (2) increased ROS levels in the mucus layer, (3) reduced Endozoicomonas relative abundance, and (4) lower growth and survival compared to ambient controls. Treatment with a specific NOX inhibitor (e.g., apocyanin) under OA will (a) normalize ROS concentrations, (b) restore mucus glycoprotein integrity (assessed by lectin staining and rheology), (c) rescue Endozoicomonas dominance (>60 % of 16S reads), and (d) significantly enhance linear extension and survival relative to OA‑only fragments.

Falsifiable outcome: If NOX inhibition fails to reduce ROS, mucus integrity, or microbiome composition, or if it does not improve growth and survival despite effective target engagement (confirmed by reduced NOX activity), the hypothesis is refuted. Conversely, a positive result would support the model that coral immune aging is driven by NOX‑mediated ROS, positioning the oxidative arm of innate immunity as a direct target for mitigating stress‑induced holobiont collapse.