Factors Influencing Glucocorticoid Treatment Response: Mechanism-Based Strategies to Overcome Glucocorticoid Resistance and Restore GRα Function.

(word count 290) Glucocorticoids (GCs) remain central to managing dysregulated systemic inflammation in critical illness, yet therapeutic response varies widely due to multifactorial glucocorticoid resistance (GCR). This chapter provides a translational framework to guide clinicians in identifying and overcoming GCR, with a central emphasis on restoring glucocorticoid receptor alpha (GRα) function. Mechanisms of resistance include reduced GRα expression, GRβ dominance, impaired nuclear translocation, oxidative stress, mitochondrial dysfunction, micronutrient depletion, and epigenetic suppression. Pharmacokinetic and pharmacodynamic barriers-such as suboptimal dosing, impaired tissue penetration, accelerated clearance, erratic dosing schedules, and premature tapering-further compromise GRα engagement and treatment efficacy. In addition, interindividual variability in GR responsiveness is shaped by genetic polymorphisms, isoform balance, and local tissue conditions, compounded by up to ten-fold variability in circulating drug levels within the same patient. This chapter outlines evidence-based strategies to optimize GC therapy, including dose refinement, continuous infusion protocols, biomarker-guided escalation, and structured tapering. Adjunctive therapies-such as antioxidants, micronutrients, probiotics, and melatonin-are also highlighted for their role in enhancing mitochondrial resilience, redox stability, and GRα signaling across key regulatory phases. Importantly, many of these disruptions-whether arising from mitochondrial dysfunction, epigenetic changes, or intestinal dysbiosis-converge on shared molecular pathways such as nuclear factor kappa-B (NF-κB) activation, mitogen-activated protein kinase (MAPK) signaling, histone deacetylase 2 (HDAC2) inhibition, and oxidative stress, all of which compromise GRα function across systems. Recognizing this mechanistic convergence helps explain the multisystem nature of steroid resistance. It supports a unified therapeutic approach that targets oxidative stress, restores mitochondrial function, modulates the microbiome, and reinforces epigenetic regulation-working together to preserve GRα signaling across affected systems. While this framework is grounded in mechanistic and translational evidence, its application in clinical practice-including tapering strategies, biomarker thresholds, and adjunctive therapies-requires validation in randomized controlled trials.