Psoriasis is a chronic, systemic, immune-mediated disease with an incidence of approximately 2%. The pathogenesis of the disease is complex and not yet fully understood. Genetic factors play a significant role in the pathogenesis of the disease. In predisposed individuals, multiple trigger factors may contribute to disease onset and exacerbations of symptoms. Environmental factors (stress, infections, certain medications, nicotinism, alcohol, obesity) play a significant role in the pathogenesis of psoriasis. In addition, epigenetic mechanisms are considered result in modulation of individual gene expression and an increased likelihood of the disease. Studies highlight the significant role of epigenetic factors in the etiology and pathogenesis of psoriasis. Epigenetic mechanisms in psoriasis include DNA methylation, histone modifications and non-coding RNAs. Epigenetic mechanisms induce gene expression changes under the influence of chemical modifications of DNA and histones, which alter chromatin structure and activate transcription factors of selected genes, thus leading to translation of new mRNA without affecting the DNA sequence. Epigenetic factors can regulate gene expression at the transcriptional (via histone modification, DNA methylation) and posttranscriptional levels (via microRNAs and long non-coding RNAs). This study aims to present and discuss the different epigenetic mechanisms in psoriasis based on a review of the available literature.

There is a growing recognition of obesity as a chronic immunometabolic disease in which impaired adipose tissue expandability contributes to a self-amplifying inflammatory network that extends across multiple organs. This state-of-the-art narrative review, the third and final part of the Prometheus’s Fire series, considers how lifestyle interventions, bariatric surgery and pharmacological therapies may disrupt this network and support the restoration of immunometabolic homeostasis. We introduce the concept of therapeutic convergence, describing how interventions with different primary mechanisms can influence shared processes, including NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome activity, adipokine dysregulation, adipose tissue remodelling, mitochondrial stress and inter-organ inflammatory signalling. Evidence from randomised controlled trials, meta-analyses and mechanistic studies shows that these interventions differ considerably in the extent and breadth of their effects. Bariatric surgery, glucagon-like peptide-1 (GLP-1) receptor agonists and double GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists (tirzepatide) have the most consistent evidence for coordinated effects on adipose tissue inflammation, metabolic dysfunction and inter-organ signalling. Other interventions appear to influence more selected components of the network and may therefore have greater value as complementary rather than comprehensive approaches. This perspective also highlights a limitation of relying on body weight as the primary measure of therapeutic success. Weight loss remains an important clinical goal, but it may not fully reflect the extent or durability of immunometabolic recovery. The therapeutic convergence framework therefore offers a way to understand how mechanistically distinct interventions can produce overlapping systemic benefits and may help identify treatment strategies that more effectively restore adipose tissue function while disrupting the inflammatory processes that sustain metabolic disease.

Obesity is a heterogeneous disease in which cardiometabolic risk is shaped not only by adipose tissue mass but also by the capacity of adipose tissue to expand and remain metabolically functional. This narrative review provides an integrated, evidence-weighted molecular framework, the central original contribution of this work, for understanding how initially adaptive adipose tissue expansion transitions into pathological hypertrophy and self-sustaining immunometabolic dysfunction. We examine how impaired adipogenesis, angiogenesis and extracellular-matrix remodelling converge with mitochondrial and endoplasmic reticulum stress, oxidative stress, hypoxia and lipotoxicity to destabilise adipocyte homeostasis. Particular attention is given to the NLRP3 inflammasome, positioned within a broader network including JNK, IKKβ/NF-κB, TLR4 and cGAS–STING signalling, as a molecular integrator of metabolic danger signals. We further explore how adipokine remodelling, loss of adiponectin-mediated protection and enhanced leptin signalling interact with immune-cell recruitment to establish self-amplifying inflammatory circuits. Evidence is stratified across experimental, translational and human levels; a summary table maps each mechanism to its strength of evidence and current clinical relevance. This framework explains metabolic phenotype heterogeneity among individuals with comparable adiposity and establishes the molecular foundation for Parts II and III of the Prometheus’s Fire series.

Obesity should no longer be regarded as a disease confined to adipose tissue. Contemporary evidence indicates that adipose tissue dysfunction can initiate a cascade of metabolic and inflammatory responses that progressively involve multiple peripheral organs. Drawing on current molecular and translational evidence, we delineate mechanisms through which lipotoxicity, oxidative and endoplasmic reticulum stress, NLRP3 inflammasome activation and adipokine dysregulation contribute to inflammatory and metabolic dysfunction in the liver, skeletal muscle, pancreatic β-cells, vascular endothelium, perivascular adipose tissue and tumour microenvironment. Once established, organ-specific processes may become partially self-reinforcing and reciprocally amplify systemic immunometabolic dysfunction. We propose the Hydra of Inflammation as an integrative framework in which peripheral organs function not only as targets of adipose tissue-derived signals but also as secondary contributors to a progressively interconnected inflammatory network. This network-based perspective may help explain the heterogeneity of obesity-associated metabolic phenotypes and supports a shift from isolated organ-centred models towards systems-level approaches. The framework integrates the adipose tissue mechanisms discussed in Part I with the therapeutic perspectives developed in Part III of the Prometheus’s Fire series.