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ObjectivesGenerative artificial intelligence (AI) models capable of producing photorealistic medical images are increasingly proposed for patient education, clinical illustration, and trainee instruction. However, their ability to accurately represent anatomically distinct disease subtypes remains unclear. This study evaluated the diagnostic accuracy of a widely used generative AI model in producing images corresponding to the five anatomical lipedema types defined by the Schmeller classification.MethodsIn this prospective audit, ChatGPT’s image-generation interface was prompted to create 60 images for each lipedema type (Types I–V),yielding 300 images. Prompts were standardized and limited to the subtype label without additional descriptors. Two clinicians independently classified each image into one of the five lipedema types or as indeterminate, blinded to the original prompt; disagreements were resolved by a third clinician. Diagnostic performance was assessed using a confusion matrix and per-type sensitivity, specificity, positive predictive value(PPV), negative predictive value (NPV),F1-score,and one-vs-rest receiver operating characteristic area under the curve (ROC AUC). Overall accuracy and Cohen’s κ statistics were also calculated.ResultsAll 300 images were evaluable. The model generated anatomically consistent images for Types I,II, and III (sensitivity = 1.00 for each). Specificity was 1.00 for Types I and II but 0.50 for Type III because all images requested as Types IV and V were classified as Type III. Consequently, the model failed to generate any images consistent with Type IV(arm-predominant) or Type V(calf-isolated) lipedema (sensitivity = 0.00 for both). Overall accuracy was 0.600. Unweighted and quadratic-weighted Cohen’s κ values were 0.500 and 0.667, respectively. Micro- and macro-averaged ROC AUC were both 0.750.ConclusionThe model reproduces severity gradients within lower-extremity lipedema but systematically collapses anatomically distinct subtypes into the dominant Type III phenotype, failing to depict arm-predominant and calf-isolated disease. Current generative AI systems may therefore encode lipedema as a single visual phenotype rather than a distributed anatomical entity, limiting their reliability for medical education and clinical communication.

Background Lipedema is a painful subcutaneous adipose tissue (SAT) disorder that mainly affects women. Patients present fat accumulation in the limbs, especially in the legs. Methods A pilot-controlled clinical trial was conducted on a sample of 18 patients with lipedema, equally divided into a control group (CG) and an experimental group (EG). Both groups were given 10 sessions of diathermy on the inner side of their knees, 10 min of treatment per knee. EG was given the diathermy dose at high-intensity heat, while CG was given sham treatment. Measurement instruments used were circumferential measurements, ultrasound measurements, algometry, VAS, and SF-12 questionnaire. Data were collected at baseline, at the end of the study and 5 weeks later. Results significant reductions in left knee circumference were observed in the EG compared with the CG (p = 0.004 post-intervention and p = 0.017 at follow-up). No significant differences were found in ultrasound, algometry, or VAS measurements within or between groups. Conclusions High-intensity heat diathermy resulted in a reduction in knee circumference, suggesting a potential effect on limb volume.

Background: Lipedema is a chronic disorder that predominantly affects women and is characterized by abnormal subcutaneous adipose tissue accumulation, pain, and vascular dysfunction. However, reliable circulating biomarkers that reflect disease-specific pathophysiology are still lacking. This study investigated serum markers associated with adipose tissue, inflammation, and angiogenesis to further elucidate the pathophysiology of lipedema. Methods: In this cross-sectional observational study, fasting serum levels of adiponectin, chemerin, lipopolysaccharide-binding protein (LBP), proprotein convertase subtilisin/kexin type 9 (PCSK9), soluble CD163 (sCD163), and soluble CD137 (sCD137)—proteins associated with obesity and inflammation—were measured in 23 premenopausal women with lipedema and 23 age-matched healthy premenopausal controls. Serum endostatin levels, an angiogenesis inhibitor, and insulin-like growth factor binding protein 2 (IGFBP2), a potent proangiogenic factor, were also assessed. Results: Patients with lipedema and obese controls had comparable body mass index, glucose, and serum lipid profiles. No significant differences were observed between groups in circulating levels of adiponectin, chemerin, LBP, PCSK9, sCD163, sCD137 and IGFBP2. In contrast, serum endostatin levels were significantly reduced in patients with lipedema (p = 0.038). Additional analyses demonstrated markedly higher endostatin expression in human subcutaneous adipose tissue than in the liver, suggesting that circulating endostatin levels may be related to adipose tissue mass. However, serum endostatin levels were lower in obese compared with normal-weight women (p < 0.001). Conclusion: Lipedema was not associated with altered circulating levels of adiponectin, chemerin, LBP, PCSK9, sCD163, sCD137 or IGFBP2. Reduced serum endostatin levels support a potential role for vascular dysfunction in the pathophysiology of lipedema.

Lipedema is a chronic disorder of subcutaneous adipose tissue characterized by disproportionate fat accumulation, pain, and progressive functional impairment, predominantly affecting women. Research remains fragmented across vascular, hormonal, metabolic, and gynecologic perspectives. Recent contributions have advanced specific axes: an international Delphi consensus, a systematic review of hormonal hypotheses, a stromal-vulnerability narrative, and a focused review of adipose biology; but no prior framework has integrated these domains into a single architecture annotated by level of evidence and capable of generating stratified, falsifiable research hypotheses. Here, we propose a hypothesis-generating translational framework that conceptualizes lipedema as the predominant adipose expression of a hormone-sensitive stromal vulnerability. The framework adds a specific molecular convergence axis, ERα/ERβ signaling imbalance interacting with intracrine steroid metabolism (aromatase, 17β-HSDs, AKR1C1), and resolves the disorder into four interacting biological pathways: (i) hormonal transition sensitivity across the female life course; (ii) metabolic– behavioral amplification; (iii) gynecologic–endocrine comorbidity; and (iv) intrinsic stromal–adipose susceptibility. The framework predicts that lipedema and its cognate expressions in hormone-responsive tissues (including gynecologic disease, connective tissue laxity, microvascular dysfunction, neurosensory amplification, and neuropsychological burden) may share a common stromal-endocrine substrate while preserving phenotypic specificity through dominant-pathway combinations. Four features distinguish this framework from prior syntheses: (a) ERα/ERβ signaling imbalance is articulated as a candidate molecular convergence axis linking adipose, gynecologic, connective-tissue, microvascular, and neuro-immune manifestations; (b) intracrine steroid metabolism (aromatase, 17β-HSDs, AKR1C1) is incorporated as the mechanistic anchor of stromal hormone-responsiveness; (c) per-component evidence-level annotation is applied throughout (Level 1A/1B: direct evidence in lipedema; Level 2: observational association; Level 3: mechanistic extrapolation); and (d) stratified, falsifiable research hypotheses are derived from dominant-pathway phenotypes. Two domains, metabolic burden and steroid signaling, emerge as promising translational research domains. Important limitations apply. Direct mechanistic evidence in lipedema-specific tissues is limited; much of the supporting biology is extrapolated from adipose, gynecologic, and metabolic literatures; and most clinical data derive from observational cohorts in referral centers. This article therefore proposes a hypothesis-generating translational framework, not a clinical guideline or therapeutic recommendation.

Lipedema is a chronic and underrecognized adipose tissue disorder in women, often misdiagnosed as obesity or lymphedema. Diagnosis is challenging due to overlapping clinical features and the lack of standardized imaging criteria. We report a 50-year-old postmenopausal woman, known hypothyroid on thyroxine and currently euthyroid, presenting with a 6-year history of progressive, symmetrical bilateral lower-limb swelling, predominantly involving the thighs and legs with sparing the feet. Body mass index was 37.8 kg/m2 (Class II obesity). Lower-limb Doppler ultrasonography excluded arterial or venous obstruction, and filarial serology was negative. Crucially, lymphoscintigraphy, a cost-effective and readily available nuclear medicine tool, demonstrated normal lymphatic drainage, excluding lymphedema and prompting whole-body dual-energy X-ray absorptiometry (DEXA) for further assessment. Whole-body DEXA revealed obesity with disproportionately increased and symmetrical lower limb fat, elevated fat mass index (16.7 kg/m2), and near-equal trunk-to-leg fat distribution, suggestive of a possible lipedema phenotype (Stage II). Magnetic resonance imaging showed extensive symmetrical fat signal intensity in the subcutaneous layer, supporting the DEXA findings. This case emphasizes the sequential role of nuclear medicine techniques—lymphoscintigraphy for functional lymphatic assessment and DEXA for quantitative body composition analysis—in the accurate diagnosis of lipedema, in an obese postmenopausal woman.

Background:Lipedema is a chronic connective tissue disorder characterized by painful subcutaneous adipose accumulation, mainly in the lower extremities. Pain is a hallmark feature, yet its mechanisms remain poorly defined. Neuropathic components may contribute, but direct comparisons with lymphedema are scarce.Methods:In this exploratory cross-sectional study, 118 female patients with lipedema (n = 62) or bilateral lower extremity lymphedema (n = 56) were assessed. Pain intensity was measured with the Visual Analogue Scale (VAS). Neuropathic pain was evaluated with painDETECT and Leeds Assessment of Neuropathic Symptoms and Signs (LANSS). Psychological status was measured using the Hospital Anxiety and Depression Scale (HADS), cognitive–emotional aspects with the Pain Catastrophizing Scale (PCS), and health-related quality of life with the WHOQOL-BREF.Results:Lipedema patients reported higher pain severity (VAS 6.2 ± 1.4 vs. 5.5 ± 1.5, p = 0.02) and greater neuropathic pain prevalence (42% vs. 21%, p < 0.01) than lymphedema. painDETECT and LANSS scores were significantly higher in lipedema (p < 0.001). HADS-Anxiety (10.2 ± 3.8 vs. 7.8 ± 3.5, p = 0.005) and PCS scores (29.5 ± 7.2 vs. 25.4 ± 6.5, p = 0.03) were also elevated, while HADS-Depression was slightly higher in lymphedema without significance. WHOQOL-BREF scores were similarly reduced in both groups compared to population norms. Correlation analyses showed strong associations between pain intensity, neuropathic features, catastrophizing, and anxiety, particularly in lipedema.Conclusions:A substantial proportion of lipedema patients exhibit neuropathic pain features and higher pain severity compared with lymphedema, while anxiety and pain catastrophizing appear to amplify symptom burden; however, quality-of-life impairment is substantial in both conditions, and the findings should be interpreted as hypothesis-generating with implications for more individualized management approaches.

Lipedema is a chronic adipose tissue disorder characterized by disproportionate and often painful enlargement of the extremities, occurring predominantly in women. Despite increasing clinical recognition, the underlying pathophysiology remains incompletely understood and is likely multifactorial. Existing evidence suggests contributions from vascular alterations, adipose tissue remodeling, inflammatory activation, hormonal influences, and lymphatic dysfunction. This review proposes a hypothesis-generating integrative framework in which lipedema may reflect a regenerative imbalance of subcutaneous adipose tissue. Within this model, genetically and hormonally modulated endothelial permeability could promote activation of perivascular adipose-derived stromal/stem-cell niches and stromal vascular fraction signaling pathways, thereby facilitating coupled angiogenesis and adipogenesis. Progressive adipocyte hyperplasia and hypertrophy may subsequently contribute to inflammatory remodeling, pain generation, and secondary impairment of dermal and subdermal lymphatic drainage. The proposed framework attempts to integrate clinical, histological, imaging, molecular, and endocrine observations into a biologically coherent conceptual model. At the same time, the review emphasizes the current limitations of the available evidence, the heterogeneity of lipedema phenotypes, and the ongoing controversies regarding disease progression, obesity overlap, and the relative role of lymphatic dysfunction. Finally, the potential mechanistic rationale of lymphatic-sparing liposuction is discussed in the context of tissue decompression, restoration of lymphatic transport, and interruption of persistent adipose remodeling. The model presented here should be interpreted as a hypothesis-generating conceptual scaffold requiring prospective validation. Importantly, the present framework should be interpreted as a biologically plausible and hypothesis-generating conceptual model rather than a definitive mechanistic doctrine. Several proposed interactions remain associative and require prospective biological validation.

Lipedema is a chronic adipose tissue condition that primarily affects women. Despite increasing recognition of lipedema, the condition remains poorly understood and lacks standardized diagnostic criteria or confirmatory tests. Variability in definitions and measurement across clinical and research settings impedes comparability across studies, constraining the evidence base needed to support future advances in clinical practice and patient care. To address challenges associated with inconsistent definitions and data collection, the Lipedema Foundation (LF) partnered with clinicians, researchers, and biostatisticians to develop a Lipedema Common Case Report Form (CCRF). The CCRF was designed to be a research data harmonization tool and is not intended to define diagnostic standards or guide clinical treatment decisions. Its development involved review of published lipedema clinical guidelines and collaborative work to define data elements and attributes for inclusion. When they existed, validated or standardized measures were incorporated directly. When no suitable standardized measures were available, an iterative and collaborative process was used to develop lipedema-specific Common Data Elements (CDEs). The initial version of the CCRF was piloted in participants with and without lipedema, and updates based on participant and clinician feedback were incorporated into the CCRF. A biostatistical review evaluated data completeness, quality, and structure, leading to additional refinements. The final Version 1 instrument consists of 682 CDEs organized into four classifications: (1) Core, (2) Supplemental Highly Recommended, (3) Supplemental, and (4) Exploratory. The current version is prepared for dissemination in the field. By disseminating the CCRF broadly and encouraging adoption in all lipedema research beginning in 2026, including all newly initiated LF-funded projects, LF intends to evaluate its use with grantees and iterate systematically to achieve consistent and comparable data collection. The CCRF provides a structured framework for harmonized data collection that may facilitate comparability across studies and support future development of standardized diagnostic and research methodologies.

Objectives: To examine the associations of ultra-processed food (UPF) consumption, dietary inflammatory index (DII), and Mediterranean diet adherence with pain severity, physical quality of life, body composition, and inflammatory markers in women with lipedema. Methods: This cross-sectional study included women diagnosed with lipedema across different disease stages. Dietary intake was assessed using a validated food frequency questionnaire, and foods were classified according to the NOVA system to determine UPF consumption. The dietary inflammatory index was calculated to assess the inflammatory potential of the diet, and Mediterranean diet adherence was evaluated using a standardized scoring system. Anthropometric measurements, body composition parameters, inflammatory markers, pain intensity (VAS), and physical quality of life (SF-12 PCS) were assessed. Multivariable regression analyses were performed to investigate the associations between dietary variables and clinical outcomes. Results: A total of 86 women with lipedema (stage 1: n=36, stage 2: n=33, stage 3: n=17) were included. UPF consumption increased from 28.1% to 41.3% of total energy and DII scores from +1.46 to +3.02 across stages, while Mediterranean diet adherence decreased from 28.2 to 21.3. In parallel, BMI increased from 27.1 to 31.1 kg/m² and body fat percentage from 36.7% to 41.1%. Inflammatory markers also rose across stages (hs-CRP: 3.9 to 6.1 mg/L; IL-6: 3.1 to 4.6 pg/mL). In multivariable models, higher DII scores were associated with increased pain severity (β=0.29, p=0.007) and higher hs-CRP levels (β=0.41, p<0.001), whereas Mediterranean diet adherence was positively associated with physical quality of life (β=0.34, p=0.002). Conclusion: Higher ultra-processed food consumption and dietary inflammatory potential were associated with increased inflammation, pain, and adiposity, whereas greater Mediterranean diet adherence was associated with better physical quality of life in women with lipedema.

Lipedema affects an estimated 11–12% of women worldwide and is characterized by bilateral, symmetric adipose deposition in the lower extremities, disproportionate pressure pain, spontaneous bruising, and resistance to conventional dietary interventions. Despite its prevalence, lipedema lacks a unifying mechanistic framework. Current descriptions treat it as a fat storage disorder with secondary vascular and inflammatory features, leaving critical observations mechanistically unexplained: a highly characteristic quantitative sensory testing (QST) pattern with no published alternative mechanistic explanation, a paradoxical immunological profile, a 35–40% comorbidity with fibromyalgia, a 1.42 relative risk for ADHD, estrogen-dependent onset, and asymmetric expression in the presence of local vascular triggers. We propose the gfWAT-IIT2 framework, which posits that lipedema is fundamentally a syndrome of polarization of the gluteofemoral white adipose tissue (gfWAT) microenvironment toward innate type 2 immunity (IIT2), amplified by estrogen via mast cell estrogen receptors, and generating neuropathic pain through selective histaminergic sensitization of Aδ/C fibers (H1/H4 receptors, PPT↓) and inhibition of Aβ fibers (H3 receptor, VDT↑), with thermal thresholds remaining normal: a triad that is mechanistically explained by histaminergic peripheral sensitization. The gfWAT-IIT2 framework integrates reported clinical, sensory, immunological, and depot-specific observations into a testable mechanistic cascade, generates fourteen falsifiable predictions, and repositions the therapeutic target from adipocyte to mast cell. The framework further proposes that asymmetric lipedema (where one limb expresses the disease more severely due to an identifiable local trigger) constitutes a natural controlled experiment suggesting that local trigger removal may be disease-modifying in selected patients with documented triggers.

Lipedema has long been misclassified as a cosmetic concern or a subtype of obesity, leading to delayed diagnosis and suboptimal surgical outcomes. Growing molecular, histopathologic, and imaging evidence supports lipedema as a systemic disorder involving adipose tissue, connective matrix, vascular–lymphatic integrity, and neuroimmune regulation. To integrate these findings into a clinically actionable model, we introduce the concept of Adipoconnective Fragility Syndrome (AFS), framing lipedema as a multisystem condition with direct implications for surgical planning and perioperative management.

INTRODUCTION: Lipedema is a chronic adipose tissue disorder characterized by disproportionate fat deposition, primarily in the lower extremities, leading to pain, functional impairment, and reduced quality of life. While Power-Assisted Liposuction (PAL) is the standard surgical approach, the integration of Ultrasound-Assisted Liposuction (UAL) with PAL has been proposed to enhance fat removal and improve patient outcomes. OBJECTIVE: To compare the clinical efficacy, postoperative outcomes, and complication rates of PAL alone versus UAL + PAL in patients with Stage II and III lipedema. METHODS: A retrospective cohort study was conducted on 60 female patients diagnosed with lipedema (Stage II and III). 30 patients underwent PAL alone, while 30 received UAL followed by PAL. Primary outcomes included the volume of fat aspirated, circumferential reduction, and postoperative pain, measured at multiple time points over a 12-month follow-up. Secondary outcomes assessed patient satisfaction, time to return to daily activities, and complication rates. RESULTS: The UAL + PAL group demonstrated a significantly higher mean fat extraction volume (5,500 ± 450 mL) compared to the PAL group (4,100 ± 380 mL; p < 0.01). Circumferential reduction was greater in the UAL + PAL group, with an average reduction of 12.5 cm versus 8.2 cm in the PAL group (p < 0.01). Postoperative pain, assessed using a Visual Analog Scale (VAS), was significantly lower in the UAL + PAL group (VAS 4.5 ± 0.7) compared to the PAL group (VAS 6.2 ± 0.8 at 24 hours post-surgery; p < 0.01). Additionally, patients treated with UAL + PAL reported a faster return to daily activities (9.3 ± 1.8 days vs. 12.8 ± 2.1 days; p < 0.01) and higher satisfaction scores (4.8 ± 0.5 vs. 4.2 ± 0.6 on a 5-point Likert scale; p < 0.05). Complication rates were comparable between the two groups, with no major adverse events reported. CONCLUSION: UAL + PAL offers significant advantages over PAL alone in the surgical management of lipedema, providing superior fat removal, reduced postoperative pain, faster recovery, and improved patient satisfaction. These findings support the integration of UAL into standard liposuction protocols for advanced-stage lipedema, emphasizing its efficacy in overcoming the challenges posed by fibrotic adipose tissue. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Introduction: Lipedema is a fat disorder in which high levels of inflammation and over proliferative adipocytes lead to accumulation of adipose tissue in peripheral limbs. Lipedema is intertwined with lymphedema, in which patients with advanced stages of lipedema often develop secondary lymphedema. The adipose tissue extracellular matrix (ECM) modulates the function of adipocytes and adipose stromal cells (ASCs). In lipedema, the aberrant adipose tissue is characterized by stiff and fibrotic nodules, suggesting changes in biochemical and mechanical properties. It is unknown how the biomechanical and biochemical composition of the ECM affects lipedema. Thus, we have developed a tissue chip format using various ECMs and stiffnesses to evaluate their effects on ASCs from both lipedema and non-lipedema patients.Hypothesis: Lipedema donor-derived ASCs have higher proliferation compared to non-lipedema cells, and stiffer substrates will have higher proliferation rates compared to softer substrates.Methods: Tissue chips were fabricated using 64 well microscale formats. Polydimethylsiloxane substrates were fabricated with three stiffnesses (150, 500, and 900 kPa). Upon surface modification by polydopamine, 31 different multi-component ECM combinations consisting of collagens 2-4, fibronectin, and laminin were immobilized. Human ASCs from lipedema or non-lipedema patients were seeded onto tissue chips (n=3), cultured for 48h, fixed, and then stained Ki67 as a proliferation marker. Ki67 expression was quantified using cellprofiler software and analyzed using R.Results and Conclusions: ASCs from non-lipedema donors showed higher Ki67 expression, compared to lipedema donors, indicating higher degree of proliferation. Additionally, 150 kPa substrates showed higher rates of proliferation compared to 900 kPa substrates, while 500 kPa substrates had moderate proliferation rates in between the other two stiffnesses. To a lesser extent, the ECM biochemical composition further influenced proliferation capacity. Contrary to our hypothesis, non-lipedema ASCs had higher proliferation rates than lipedema ASCs, and softer substrates had higher rates of proliferation than stiffer substrates. As lipedema adipocytes are hypertrophic, we expected that lipedema derived ASCs would have higher rates of proliferation compared to non-lipedema ASCs. Additional analysis of other metrics of lipedema (ie inflammation) and further interrogation of lymphatic function are warranted.Open in Viewer

Lymphedema and Lipedema are chronic disorders that are often misdiagnosed, leading to complications ranging from infection to impaired mobility. While the genetic basis of lymphedema is well characterized, the genetic contributions to lipedema remain unclear despite clear familial hereditary patterns. This review examines current knowledge on the genetic foundations of both conditions, examining established causative genes in lymphedema and emerging evidence of heritability in lipedema. It also evaluates the role of genetic testing in diagnosis and classification. By emphasizing established findings and highlighting ongoing gaps, this review supports efforts to refine diagnosis and guide therapeutic development.

Lipedema is a chronic and progressive adipose tissue disorder characterized by disproportionate fat accumulation, microvascular dysfunction, chronic inflammation, and progressive fibrosis. Despite its prevalence and significant impact on quality of life, current therapeutic approaches remain largely symptomatic and fail to address the underlying biological mechanisms of the disease. Emerging evidence suggests that lipedema should be understood as a multifactorial condition involving genetic susceptibility, endothelial alterations, immune dysregulation, and extracellular matrix remodeling. In this context, pharmacological strategies targeting these pathways have gained increasing attention. Metformin, through activation of AMP-activated protein kinase (AMPK), exerts antifibrotic and immunometabolic effects, including inhibition of TGF-β signaling, reduction of extracellular matrix deposition, and modulation of adipose tissue inflammation. In parallel, incretin-based therapies, particularly glucagon-like peptide-1 (GLP-1) receptor agonists and dual GLP-1/GIP agonists such as tirzepatide, have demonstrated pleiotropic effects that extend beyond weight reduction, including improvements in metabolic homeostasis, reduction of systemic inflammation, and enhancement of endothelial function. These therapies appear to act through complementary mechanisms, with metformin primarily targeting tissue remodeling and fibrosis, and incretin-based therapies exerting broader systemic effects on metabolism, inflammation, and vascular integrity. This review proposes a hypothesis-generating mechanistic framework, supporting a shift from weight-centric and symptomatic approaches toward disease-modifying strategies. Although current evidence in lipedema is largely indirect, the convergence of experimental and clinical data provides a strong rationale for further investigation. Future studies should focus on evaluating combined therapeutic approaches and identifying biomarkers that reflect fibrosis, inflammation, and microvascular dysfunction, with the aim of developing targeted and personalized treatments for this complex disorder.

Lipedema is a chronic, multifactorial disorder characterized by connective tissue dysregulation, in which vascular dysfunction plays a significant role. Lipedema manifests as symmetrical, painful accumulation of adipose tissue, predominantly in the lower body and arms, with progressive pain, tissue heaviness, and soft-tissue changes across disease stages. Emerging evidence from the micro-to macro-scale implicates endothelial dysfunction, aberrant angiogenesis, and vessel fragility in the pathological accumulation of interstitial fluid leading to tissue edema. Vascular changes are compounded with extracellular matrix remodeling in the form of adipose tissue expansion and fibrosis. Immune cell infiltration and chronic inflammation further contribute to tissue stiffening and adipose hypertrophy, highlighting the role of immune-mediated mechanisms in disease progression. The interplay between vascular, lymphatic, connective tissue, and immune dysfunction emerges as a central determinant of lipedema pathophysiology. Understanding these interconnected mechanisms is critical for elucidating the fundamental biology of lipedema, identifying novel biomarkers, and guiding the development of translational interventions and optimized clinical management strategies.