AbstractHuman fertility is regulated by a complex, integrated network of biological systems that collectively determine reproductive competence in males and females. Conventional fertility assessment relies on established clinical biomarkers, including reproductive hormone profiles, gamete-based functional assessments and imaging indicators of gonadal structure and function. While clinically informative, these measures capture only partial views of molecular and cellular processes underlying gametogenesis and reproductive capacity. Recent advances in reproductive medicine have expanded the biomarker landscape through genetic and epigenetic profiling, enabling identification of pathogenic variants, chromosomal abnormalities and regulatory modifications associated with infertility syndromes. In parallel, multi-omics approaches are increasingly being used to characterize molecular networks governing gamete development, meiotic integrity, DNA repair and cellular differentiation. This review presents a comprehensive synthesis of fertility biomarkers, spanning endocrine, genetic, epigenetic, structural, metabolic and inflammatory systems. Current evidence is examined on endocrine and reproductive hormone biomarkers, followed by an investigation of genetic and epigenetic markers of reproductive dysfunction, as well as structural and imaging-based biomarkers and inflammatory and metabolic indicators. Finally, emerging biomarker platforms are highlighted as key advances towards precision reproductive medicine. Collectively, these developments support a shift towards a more comprehensive, biomarker-driven framework for the evaluation and management of infertility.
Abstract Heat shock protein 90 (Hsp90) is a ubiquitous molecular chaperone that governs the folding, stabilization and activity of a wide range of client proteins, many of which are critical regulators of immune cell signalling and inflammatory responses. Recent research has underscored the role of Hsp90 in orchestrating both innate and adaptive immune functions, particularly in the context of autoimmune diseases. In autoimmune diseases, dysregulated immune pathways often involve Hsp90-dependent client proteins, including key kinases and transcription factors. By modulating the activation, differentiation and survival of immune cells Hsp90 emerges as a central node in autoimmune pathogenesis. Importantly, the pharmacological inhibition of Hsp90 has shown promise in preclinical models of autoimmunity, where it attenuates pro-inflammatory pathways. In this review, we examine the immunoregulatory functions of Hsp90 with a focus on autoimmune disorders, highlighting its role in disease-driving pathways, such as Nuclear Factor Kappa B (NF-κB), Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) and Mitogen-Activated Protein Kinase (MAPK). We also discuss the current landscape of Hsp90 inhibitors, their mechanism of action, and emerging data on their efficacy in autoimmune disease models. Understanding how Hsp90 shapes immune cell behaviour and inflammation provides a compelling framework for its development as a novel therapeutic target in chronic autoimmune conditions.
AbstractHeat shock protein 90 (Hsp90) is a ubiquitous molecular chaperone that governs the folding, stabilization and activity of a wide range of client proteins, many of which are critical regulators of immune cell signalling and inflammatory responses. Recent research has underscored the role of Hsp90 in orchestrating both innate and adaptive immune functions, particularly in the context of autoimmune diseases. In autoimmune diseases, dysregulated immune pathways often involve Hsp90-dependent client proteins, including key kinases and transcription factors. By modulating the activation, differentiation and survival of immune cells Hsp90 emerges as a central node in autoimmune pathogenesis. Importantly, the pharmacological inhibition of Hsp90 has shown promise in preclinical models of autoimmunity, where it attenuates pro-inflammatory pathways. In this review, we examine the immunoregulatory functions of Hsp90 with a focus on autoimmune disorders, highlighting its role in disease-driving pathways, such as Nuclear Factor Kappa B (NF-κB), Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) and Mitogen-Activated Protein Kinase (MAPK). We also discuss the current landscape of Hsp90 inhibitors, their mechanism of action, and emerging data on their efficacy in autoimmune disease models. Understanding how Hsp90 shapes immune cell behaviour and inflammation provides a compelling framework for its development as a novel therapeutic target in chronic autoimmune conditions.
AbstractInsulin is a central regulator of metabolic homoeostasis with diverse, tissue-specific actions across multiple organs. Despite major advances in insulin formulations, current therapies rely on systemic delivery and do not reproduce the physiological distribution of endogenous insulin, resulting in non-physiological tissue exposure and associated metabolic limitations. In this perspective, we discuss emerging strategies aimed at achieving tissue-selective insulin action, including molecular engineering of insulin analogues, modulation of insulin receptor isoform specificity and targeted delivery approaches. Attention is given to hepato-preferential, muscle-directed, brain-targeted and adipose-modulating strategies, highlighting their mechanistic basis, therapeutic potential and inherent limitations. While proof of principle has been established for several approaches, challenges remain in balancing tissue selectivity with whole-body metabolic control. Advances in protein design and delivery technologies may ultimately enable the development of next-generation insulin therapies that better mimic physiological insulin action and improve clinical outcomes in metabolic and neurodegenerative diseases.
Abstract In mammalian preimplantation embryos, distinct cell lineages occupy defined spatial niches. The outer trophectoderm (TE) forms an epithelial monolayer surrounding the inner cell mass (ICM) and blastocyst cavity. In mice, the Tead4 gene encodes a polarity-dependent transcription factor required for TE specification. Here, we demonstrate that Tead4 also preserves TE integrity during blastocyst maturation. Clonal siRNA-mediated Tead4 knockdown (KD) disrupts outer cell apical domain morphology, causing abnormal allocation of these clones to an enlarged ICM, despite minimal impact on established polarity. Fixed sample and live embryo light-sheet microscopy imaging reveal that TEAD4-deficient outer cells atypically migrate into the blastocyst ICM, sometimes via apical domain abscission, or are repositioned post-division, linking disrupted apical domain morphology to altered spatial positioning and fate. Transcriptomic analysis indicates that TEAD4 regulates genes involved in cytoskeletal organization, particularly those related to actin and cell adhesion, which we propose are critical for maintaining outer cell TE positioning. Combined KD of Tead4 and two of its targets, the atypical GTPases Rnd1 and Rnd3, partially rescues misallocation but does not prevent apical morphological abnormalities. These findings indicate TEAD4 and its downstream regulatory network actively contribute to blastocyst TE maintenance, beyond initial specification, up until the peri-implantation stage, ensuring proper lineage segregation.
