Search Results (454)

Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the leading causes of chronic liver disease worldwide, and effective pharmacological therapies remain limited. Pemafibrate (Pema), a selective peroxisome proliferator-activated receptor alpha (PPARα) modulator (SPPARMα), has shown promising therapeutic potential in patients with MASLD and hypertriglyceridemia; however, its underlying mechanisms remain incompletely understood. Here, we investigated the therapeutic effects and molecular mechanisms of Pema using in vitro and in vivo MASLD models and evaluated its clinical relevance in patients with MASLD. In a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD)-induced MASLD mouse model, Pema dose-dependently ameliorated hepatic steatosis and fibrosis and significantly suppressed the hepatic expression of inflammatory and fibrogenic genes, including TLR4, TNFα, αSMA, and Col1A1. Pema also favorably altered the gut microbiota by increasing the abundance of the phylum Verrucomicrobia, suggesting modulation of the gut–liver axis. In differentiated 3T3-L1 adipocyte-like cells, Pema induced PPARα expression, inhibited insulin-mediated EGR-1 induction, and significantly reduced leptin secretion. Consistent with these findings, serum insulin and leptin levels, as well as the hepatic accumulation of both molecules, were markedly decreased in Pema-treated MASLD mice. Furthermore, in a clinical cohort of 192 patients with MASLD and hypertriglyceridemia, long-term Pema treatment significantly improved liver-related biochemical parameters, insulin resistance, surrogate markers of liver fibrosis, and serum leptin levels. Collectively, these findings demonstrate that Pema attenuates MASLD progression by suppressing leptin-mediated metabolic and inflammatory signaling while improving the gut microenvironment. These results highlight SPPARMα as a promising therapeutic strategy for MASLD and support further clinical investigation of Pema as a disease-modifying treatment targeting the gut–liver axis. Full article

Ageing and obesity represent major public health challenges and are associated with metabolic dysfunction, chronic inflammation, and loss of skeletal muscle mass. Resistance training (RT) is an effective strategy to increase muscle mass; however, its effects on metabolic and immune parameters in older women with obesity remain unclear. The study aimed to compare the effects of 12-week progressive overload RT programme on metabolic and immune responses in women aged 60–79 years with obesity and normal-weight women. Thirty older women were allocated into two groups according to body composition: women with obesity (OB: 68 ± 4.21 years; body mass index [BMI] = 33.01 ± 2.62 kg/m²; body fat percentage = 42.23% ± 2.98%; n = 16) and normal-weight women (NW: 66 ± 4.31 years; BMI = 22.60 ± 1.36 kg/m²; body fat percentage = 33.11% ± 3.61%; n = 14). At baseline, the OB group showed higher serum concentrations of leptin, insulin, triglycerides, and HOMA-IR and lower HDL cholesterol concentrations compared with the NW group, while no differences were observed in circulating cytokines or NETosis. After 12 weeks of RT, fasting glucose decreased only in the OB group (p = 0.030). Both groups exhibited reductions in total cholesterol and adiponectin, along with an increase in NETosis. Leptin, insulin, and pro-inflammatory cytokines were associated with lower muscle quality, whereas higher baseline adiponectin concentrations were associated with greater muscle mass gains in the NW group (p < 0.05). In conclusion, baseline metabolic differences were observed between normal-weight older women and those with obesity; however, both groups showed changes after 12 weeks of RT in metabolic and immune parameters. Furthermore, higher baseline adiponectin concentrations were associated with greater muscle mass gains in the NW group. Full article

In 1994, leptin was identified as a hormone that signals the brain to reduce food intake and increase energy expenditure. Leptin was initially considered a breakthrough therapy for obesity. This was largely based on animal studies, showing that leptin reversed obesity in individuals with congenital leptin deficiency and normal leptin receptor sensitivity. However, due to leptin resistance, leptin therapy failed to reduce weight in common human obesity. Consequently, interest in leptin waned for many years. However, recent studies in animal models of common obesity show that combining leptin with other weight-loss-stimulating agents, can restore hypothalamic leptin sensitivity and induce a greater reduction of body weight than after single drug treatment. Moreover, after initially reducing weight by combination therapy, leptin monotherapy proved enough to maintain reduced body weight. The strongest evidence for restoring leptin’s weight-lowering actions in common obesity to date comes from mouse studies in which leptin was combined with other pharmacotherapies. However, it is unclear at this moment whether this strategy also can be used to treat common human obesity successfully. Overcoming leptin resistance, by combining leptin with other pharmacotherapies, is a promising strategy that needs to be further investigated in humans with obesity. Full article

Background/Objectives: Insulin resistance (IR) plays a central role in metabolic dysfunction and elevates the risk of chronic diseases such as type 2 diabetes mellitus in later life. Early identification of IR in adolescents is therefore important. This study aimed to determine the triglyceride-to-high-density lipoprotein cholesterol (TG:HDL-C) ratio cutoff for IR and assess its association with IR predictors among adolescents with obesity. Methods: A total of 215 blood samples from adolescents aged 13–16 years with obesity were analyzed for fasting blood glucose, lipids, insulin, leptin, and adiponectin. Obesity was defined using BMI z-scores, while IR was classified using the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR ≥ 4.0). Receiver operating characteristic (ROC) analysis was performed to compare the discriminatory performance between the TG:HDL-C ratio and Leptin:Adiponectin ratio (LAR). Multiple logistic regression was performed to assess associations between the TG:HDL-C ratio and IR-related markers. Results: The area under the ROC curve for the TG:HDL-C ratio was comparable to LAR (0.73 vs. 0.68, p = 0.3). The optimal TG:HDL-C ratio cutoff identified using the maximum Youden index was 0.89, with 62% sensitivity and 75% specificity. A TG:HDL-C ratio ≥ 0.89 was associated with higher odds of elevated insulin (AOR 1.1, 95% CI 1.0–1.13), elevated HbA1c (AOR 2.7, 95% CI 1.1–6.6), abdominal obesity (AOR 3.6, 95% CI 1.9–6.7), and raised LAR (AOR 1.2, 95% CI 1.0–1.5). Conclusions: These findings suggest that a TG:HDL-C ratio cutoff of 0.89 may be a useful marker for identifying IR in adolescents with obesity. Full article

Background/Objectives: Omega-3 and omega-9 fatty acid supplementation has shown metabolic and immunomodulatory benefits, but evidence in pediatric insulin resistance is limited, and the persistence of effects after treatment discontinuation remains uncharacterized. This study evaluated the independent and combined effects of omega-3 and omega-9 supplementation on the metabolic and inflammatory profile of children with obesity and insulin resistance, during and after active treatment. Methods: This prespecified secondary analysis of a multicenter, randomized, triple-blind, three-arm parallel trial (NCT05488223) included 97 children (8–17 years) with overweight/obesity and baseline insulin resistance (HOMA-IR > 3.0). Participants received 1.8 g/day of omega-3 (n = 32), omega-9 (n = 34), or combined supplementation (n = 31) for 3 months, followed by a 2-month post-intervention follow-up. Metabolic and inflammatory markers were assessed at baseline (T1), end of treatment (T2), and follow-up (T3). The primary outcome was the change in HOMA-IR from T1 to T2. Results: Active supplementation significantly reduced fasting insulin and HOMA-IR in the Combined (p < 0.001) and Omega-9 (p = 0.010 and p = 0.006) groups; at month 5, only the Combined group maintained significant reductions in both. IL-6 and leptin decreased across all groups during intervention and remained reduced at follow-up. Multivariable regression (n = 96) showed the metabolic response was most strongly associated with baseline metabolic status and concurrent BMI reduction rather than intervention group, which was not an independent predictor of metabolic response, nor consistently of inflammatory outcomes (one exception: a smaller IL-4 increase with omega-9, p = 0.043, unconfirmed in GEE). Conclusions: Within-group reductions in HOMA-IR and fasting insulin persisted after discontinuation only in the Combined group, but without significant between-group differences at any timepoint, consistent with response magnitude reflecting baseline status and adiposity reduction rather than treatment group per se. This positions combined supplementation as a potential metabolic adjuvant—not a standalone therapy—for HOMA-IR-defined insulin resistance in pediatric obesity, assessed here via anthropometric and biochemical rather than imaging-based measures. Full article

Obesity is a multifactorial condition characterized by profound metabolic and inflammatory dysregulation that alters the adipose tissue-central nervous system (CNS) relationship. This paper critically summarizes the biochemical and cellular mechanisms governing this bidirectional crosstalk, moving beyond a descriptive perspective to propose an integrated model of peripheral-central interaction. White adipose tissue (WAT) and brown adipose tissue (BAT), modulated by the sympathetic nervous system (SNS), communicate with hypothalamic circuits (POMC and AgRP neurons) both through traditional endocrine signals (leptin, adiponectin, resistin, apelin) and through lipid mediators and extracellular vesicles (EVs) capable of crossing the blood–brain barrier (BBB). Under conditions of nutritional excess, the accumulation of lipotoxic lipid species (such as palmitate and ceramides) and the inflammatory polarization of brain macrophages (M1/BAMs) induce mitochondrial stress and central resistance to leptin and insulin, altering the adiposity set point. In parallel, we review emerging nutritional strategies based on polyunsaturated fatty acids (PUFAs), polyphenols, and short-chain fatty acids (SCFAs), and critically evaluate innovative technological platforms (nanoencapsulation, precision fermentation, and 3D food printing) designed to optimize nutrient bioaccessibility and restore adipose-CNS axis homeostasis, discussing current challenges for clinical translation. Full article

Obesity is associated with metabolic dysregulation and impaired male reproductive capacity, where the gut microbiota affects male reproductive function through diverse mechanisms that warrant further elucidation. This study aims to evaluate the effects of ketogenic and vegan dietary interventions in attenuating obesity-associated testicular injury and to examine the extent to which specific gut microbiota profiles mediate their impact. Forty-nine male adult albino rats were assigned to seven groups: control group, obese group (HFD), obese group + modified microbiota, obese group + ketogenic diet, obese group + ketogenic diet + modified microbiota, obese group + vegan diet, and obese group + vegan diet + modified microbiota. Metabolic markers (glucose, insulin, leptin, and HOMA-IR), reproductive hormones (testosterone, FSH, and LH), and testicular gene expression (IL-6, eNOS, and androgen receptor) were analyzed over five months. Gut microbiota composition (qPCR) and testicular histology/immunohistochemistry were assessed. HFD-fed rats exhibited hyperglycemia, insulin resistance, hypogonadism, and testicular degeneration. Both diets improved metabolic and hormonal profiles, restored testicular architecture, and downregulated inflammatory genes. Microbiota modification additively enhanced these effects, increasing the abundance of Lactobacillus and Akkermansia while reducing inflammation. The vegan diet showed superior efficacy in improving metabolic parameters, modulating pituitary–gonadal hormones, and attenuating testicular structural and functional alterations. Our findings demonstrate that ketogenic and vegan diets alleviate obesity-induced testicular dysfunction and that microbiota modulation amplifies these benefits by regulating the gut–testicular axis. Integrating dietary and microbial interventions may provide a basis for a promising approach to managing obesity-related male infertility. Full article

Obesity is a multifactorial condition that profoundly affects female reproductive health through endocrine, metabolic, and inflammatory mechanisms that disrupt the hypothalamic–pituitary–gonadal (HPG) axis. Women with obesity frequently develop menstrual irregularities, anovulation, amenorrhea, infertility, polycystic ovary syndrome (PCOS), impaired endometrial receptivity, and adverse pregnancy outcomes. Central obesity and insulin resistance contribute to hyperinsulinemia, reduced sex hormone-binding globulin (SHBG) levels, hyperandrogenism, altered gonadotropin secretion, and impaired folliculogenesis, while adipokines such as leptin and chronic inflammation further impair ovarian steroidogenesis and ovulatory function. Obesity-related oxidative stress and lipotoxicity also negatively affect oocyte quality, embryo development, implantation, and assisted reproductive technology outcomes, increasing the risk of gestational diabetes, preeclampsia, miscarriage, and preterm birth. This review evaluates the therapeutic potential of pharmacological weight-loss therapies in obesity-associated female reproductive dysfunction. A comprehensive literature review was conducted using various databases, focusing on anti-obesity pharmacotherapy on obesity, infertility and fertility in reproductive-aged women. Evidence suggests that several FDA-approved and off-label anti-obesity agents, including orlistat, liraglutide, semaglutide, phentermine/topiramate, bupropion/naltrexone, metformin, exenatide, and tirzepatide, may improve reproductive outcomes primarily indirectly through weight reduction and metabolic improvement. GLP-1 receptor agonists, particularly liraglutide, semaglutide, and exenatide, appear especially promising, demonstrating beneficial effects on insulin sensitivity, menstrual regularity, ovulation, androgen levels, and pregnancy rates in women with PCOS. Tirzepatide, a dual GLP-1/GIP receptor agonist, has shown potent weight-loss and metabolic effects with potential indirect fertility benefits. Metformin improves insulin sensitivity and is widely used in PCOS to regulate androgen levels and restore ovulation, although its effects on pregnancy and live birth rates remain controversial. However, evidence for several agents remains limited, and concerns persist regarding reproductive safety during pregnancy. Overall, anti-obesity pharmacotherapy may represent an important adjunctive strategy for improving reproductive and metabolic health in women with obesity, although larger randomized clinical trials are still required. Full article

Background: Obesity-linked anxiety may involve leptin resistance, impairing serotonin (5-hydroxytryptamine; 5-HT) signaling. In addition to drugs, nutraceuticals have been explored for their potential to address this pathophysiology. Herein, natural honey and its glycoproteins were assessed for their roles in modulating the leptin–serotonin axis to alleviate metabolic and anxiety-related disturbances. Methodology: Sixty Wistar rats were allocated to two groups (n = 30 each), one on a normal diet (ND) and the other on a high-fat diet (HFD), for four weeks to induce obesity. Each group was further divided into five sub-groups (n = 6 each) as follows: saline, low honey dose (LHD, 1 g/kg), high honey dose (HHD, 2 g/kg), low protein dose (LPD, 0.25 mg/kg), and high protein dose (HPD, 0.5 mg/kg), while continuing on the ND or HFD. The interventions were administered for four weeks. Body weight and behavioral activities were measured weekly, whereas serum leptin and triglycerides, and brain 5-HT and its primary metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were measured at sacrifice. Statistical analyses were performed using ANOVA, Tukey’s post hoc test, and correlation analyses. Results: The HFD induced leptin-driven metabolic dysfunction and serotonergic disruption, exacerbating anxiety-like behavior and locomotor deficits compared with the ND rats (p < 0.05). HHD produced a dual metabolic–neurochemical improvement by reducing hyperleptinemia, elevating 5-HT, and restoring locomotor activity while reducing anxiety-like behavior. In contrast, HPD increased 5-HIAA without altering 5-HT, reflecting an imbalanced serotonin turnover that yielded only partial anxiolytic effects. Overall, HHD partially reversed HFD-induced pathology through leptin–serotonin crosstalk, whereas HPD provided more targeted neurochemical modulation. Conclusions: Natural honey and its glycoproteins attenuate HFD-induced metabolic dysregulation and anxiety-like behavior by counteracting hyperleptinemia and enhancing serotonin synthesis. These findings highlight the potential of diet-personalized, honey-based interventions for metabolic–CNS comorbidities, warranting validation through clinical trials. Full article

Leptin is the oldest studied adipokine, and its mechanism of action in the regulation of energy metabolism remains a hot topic of current research. In this paper, we systematically review the progress of clinical and basic research on leptin and energy metabolism from 1994 to 2026. It is shown that leptin can regulate the energy metabolism homeostasis through autocrine, paracrine and neurohumoral pathways (e.g., hypothalamic–leptin–melanocortin axis). In addition, the effects of mainstream weight loss strategies such as dietary control, pharmacological interventions and exercise on leptin levels, and their underlying mechanisms were investigated in this paper, with the aim of providing a theoretical basis for the clinical application of leptin in metabolic diseases (e.g., obesity, diabetes mellitus). Future studies need to further clarify the molecular mechanisms of leptin resistance and explore precise intervention strategies based on the leptin signaling pathway. Full article

Metabolic risk increases with age and may be accompanied by changes in adipocytokine secretion and insulin sensitivity. The primary exploratory aim of this prospective, uncon-trolled study was to determine whether repeated whole-body cryotherapy (WBC) changes circulating meteorin-like hormone (METRNL) concentrations in women of different ages. Secondary exploratory outcomes included irisin, asprosin, leptin, adiponectin, insulin, fasting blood glucose (FBG), lipid profile, homeostasis model assessment of insulin resistance (HOMA-IR), triglyceride–glucose index (TyG), atherogenic index of plasma (AIP), and the leptin/adiponectin ratio. A total of 48 women were divided into three groups: GR-60 (60–70 years, n = 14), GR-40 (40–50 years, n = 18), and GR-20 (20–30 years, n = 16). Participants underwent 30 WBC sessions, each lasting 3 min at minus 120 °C. Blood samples were collected before the first WBC session, after the 10th, 20th, and 30th sessions, and two weeks after the final session. Repeated WBC did not significantly change circulating METRNL or other adipocytokines in any age group. A preliminary decrease in insulin concentration and HOMA-IR was observed after 20 WBC sessions only in GR-60. These findings suggest that repeated WBC may be associated with favorable changes in selected insulin-resistance markers in older postmenopausal women; however, the absence of a non-WBC control group, small subgroup sizes, and the multiplicity burden preclude causal or therapeutic conclusions. Randomized controlled studies are needed to verify these exploratory observations. Full article

Introduction: The widespread use of digital devices has significantly increased screen time among children and adolescents, raising concerns about its effects on dietary behaviors and health outcomes. This narrative review aimed to examine the relationship between screen exposure, unhealthy eating behaviors, and associated physical and mental health risks in pediatric populations. Methods: A narrative review of the literature was conducted using PubMed, Scopus, and Web of Science databases, with the final search updated on 30 April 2026. Studies involving individuals aged 0–18 years were included if they investigated screen time, dietary behaviors, obesity, cardiometabolic risk, sleep, or mental health outcomes. Observational studies, interventional studies, systematic reviews, and meta-analyses were considered. Findings were synthesized qualitatively according to pre-specified thematic domains, with greater interpretive weight given to systematic reviews, meta-analyses, randomized trials, longitudinal cohorts, and large population-based studies. Results: Excessive screen time was consistently associated with unhealthy eating behaviors, including increased snacking, mindless eating, breakfast skipping, and higher consumption of ultra-processed and energy-dense foods. Digital food marketing and exposure to food advertising may influence children’s food preferences and intake. High screen exposure was also associated with sedentary behavior, sleep disturbances, circadian dysregulation, and altered appetite-related hormones such as leptin and ghrelin. These pathways may contribute to, or be consistent with, obesity, insulin resistance, dyslipidemia, hypertension, and metabolic syndrome, although most evidence remains observational. Moreover, excessive screen use was associated with anxiety, depression, emotional eating, binge-eating behaviors, and body image dissatisfaction, particularly among adolescents. Conclusions: Screen time may represent a modifiable behavioral and environmental correlate of dietary habits, metabolic health, and psychological wellbeing in children and adolescents. Prevention strategies should focus not only on reducing screen duration but also on improving the quality and context of media use through family-based interventions, school programs, digital literacy, promotion of physical activity, and regulation of digital food marketing. Further longitudinal and interventional studies are needed to clarify causal relationships and develop effective prevention strategies. Full article

Obesity exhibits pronounced sex-dependent differences in susceptibility and progression; however, the molecular mechanisms coordinating central energy sensing with peripheral thermogenic responses remain incompletely defined. Selenoprotein F (SELENOF), an endoplasmic reticulum (ER)-resident member of the selenoprotein family involved in protein quality control and redox-sensitive metabolic regulation, has not previously been investigated in the context of diet-induced obesity. In the present study, WT and SELENOF-deficient mice subjected to a 16-week high-fat diet (HFD) were combined with primary brown adipocyte experiments to determine the role of SELENOF in systemic metabolic homeostasis. SELENOF deficiency markedly aggravated HFD-induced weight gain, adipose tissue expansion, dyslipidemia, and hyperleptinemia selectively in female mice, whereas no genotype-dependent effects were observed in males. Mechanistically, SELENOF deficiency intensified hypothalamic ER stress and leptin resistance, as reflected by increased GRP78, p-IRE1α, and p-PERK expression together with SOCS3 upregulation, reduced STAT3 phosphorylation, and activation of the IKK/NF-κB inflammatory pathway. In parallel, SELENOF deficiency reduced circulating free triiodothyronine (FT₃) levels and the ratio of free triiodothyronine to free thyroxine (FT₃/FT₄ ratio), and suppressed DIO2 and UCP1 expression in brown adipose tissue (BAT). Experiments in primary brown adipocytes further showed that SELENOF deficiency did not disrupt proximal β3-adrenergic signaling but attenuated the downstream induction of DIO2 and UCP1. Collectively, these findings provide preliminary evidence that SELENOF is associated with sex-dependent metabolic adaptation during HFD-induced stress by linking hypothalamic proteostasis with the thyroid hormone-related thermogenic signaling program in BAT. Full article

Background: Appetite regulation is governed by a complex neuroendocrine network that integrates peripheral peptide signals with hypothalamic and brainstem circuits to coordinate energy intake and maintain energy homeostasis. Disruption of these pathways contributes to obesity and other disorders characterised by dysregulated feeding behaviour. Objective: To map and synthesise the current evidence on the role of appetite-regulating peptide hormones and central neural pathways in appetite control, obesity pathophysiology, and emerging therapeutic approaches. Methods: A scoping review of the literature was conducted to identify and synthesise evidence relating to the physiological and pathological mechanisms of appetite regulation. The review examined the actions of key peptide hormones, including ghrelin, glucagon-like peptide-1 (GLP-1), peptide YY (PYY), leptin, and insulin, their interactions within the gut–brain axis, and their effects on central appetite-regulating circuits. Results: The evidence highlights the central role of the arcuate nucleus in integrating peripheral hormonal signals with neural pathways controlling feeding behaviour. Appetite regulation is mediated by the balance between orexigenic neuropeptide Y/agouti-related peptide (NPY/AgRP) neurons and anorexigenic pro-opiomelanocortin/cocaine- and amphetamine-regulated transcript (POMC/CART) neurons, with further modulation by the paraventricular, lateral, and ventromedial hypothalamic nuclei. The literature identifies hormone resistance, impaired satiety signalling, and altered neuroendocrine feedback as major contributors to obesity. Evidence on therapeutic interventions demonstrates the potential of GLP-1 receptor agonists, including liraglutide and semaglutide, and the dual incretin agonist tirzepatide, while also highlighting challenges related to treatment durability, adverse effects, and weight regain following discontinuation. Conclusions: Current evidence demonstrates that appetite regulation involves highly interconnected peripheral and central signalling pathways. The reviewed literature supports the development of multi-target and precision-based therapeutic strategies for obesity and identifies important areas for future research, including mechanisms of treatment resistance, long-term efficacy, and inter-individual variability in neuroendocrine responses. Full article

Obesity is a major global health challenge strongly associated with increased cardiometabolic morbidity and mortality. In men, obesity is characterized by a predominance of visceral adiposity, which is metabolically active and closely linked to systemic inflammation, hormonal dysregulation, and adverse cardiovascular outcomes. Despite its clinical relevance, male obesity remains underrecognized as a distinct pathophysiological condition. This study aimed to analyze the inflammatory mechanisms underlying male obesity and their relationship with cardiometabolic risk. A structured narrative review was conducted based on a PICo-guided research question, with literature searches performed in PubMed/MEDLINE, Scopus, Web of Science, Embase, and ScienceDirect, covering publications from 2015 to 2026. Studies focusing on male obesity, inflammatory pathways, and cardiometabolic outcomes were included. Evidence indicates that visceral adipose tissue acts as an active endocrine organ, releasing pro-inflammatory cytokines such as TNF-α and IL-6, contributing to chronic low-grade inflammation. This inflammatory state is associated with insulin resistance (IR), endothelial dysfunction, and oxidative stress, mediated by intracellular pathways including NF-κB and JNK. Additionally, adipokine imbalance, characterized by reduced adiponectin and increased leptin levels, further exacerbates metabolic and vascular impairment. Hormonal alterations, particularly reduced testosterone levels, play a key role in amplifying visceral fat accumulation and inflammation, creating a bidirectional relationship between hypogonadism and metabolic dysfunction. Clinically, these mechanisms highlight the importance of integrating inflammatory biomarkers, body composition assessment, and hormonal evaluation into the management of male obesity. Emerging therapies, including GLP-1 receptor agonists and immunometabolic interventions, offer promising strategies for reducing cardiometabolic risk. In conclusion, male obesity represents a complex, inflammation-driven condition requiring a comprehensive and mechanism-based approach to improve clinical outcomes and guide future therapeutic developments. Full article