The molecular regulators behind the pathogenesis of keloid have not been fully determined. Through Mendelian randomization and multiomics analyses, we identified retinoic acid receptor responder 2 (RARRES2) as a causal risk factor for keloid. We further found that RARRES2 is mainly enriched in fibroblasts in various human tissues. RARRES2 is highly expressed in keloid tissue and mainly enriched in fibroblasts of keloid. Heparan sulfate proteoglycan 2 (HSPG2) was identified as a potential downstream effector molecule of RARRES2, and p-STAT3 was proven to bind to the promoter region of HSPG2. We demonstrated that RARRES2 promotes the expression of HSPG2 by phosphorylating STAT3. Moreover, we confirmed that RARRES2 exerts the pro-scarring effect through the STAT3/HSPG2 pathway in primary fibroblasts and animal models. Overall, our results demonstrate that RARRES2 is a key regulator of keloid pathogenesis through STAT3-mediated HSPG2 activation, and RARRES2 can serve as a specific molecular target in patients with keloid.

Global Burden of Disease (GBD) analyses of orofacial clefts often treat modeled disability-adjusted life-year (DALY) rates or quality-of-care indices as representing untreated disease or care quality. We tested whether an incidence-adjusted residual of GBD 2023 cleft estimates can support the reading for the craniofacial program targeting. Age-standardized estimates for 204 locations (1990–2023) were linked to World Bank indicators. The residual was the ordinary least squares remainder from a quadratic in year and World Bank region, fitted to log DALY rate on log incidence, using 6800 country-years (200 countries). The residual is not a validated measure of health-system or surgical access. A country-level age-matched residual could not be computed from the GBD country extract. Adding log incidence raised R ² from 0.491 to 0.551 (incremental R ² =0.060). The incidence coefficient was 0.723 (country-clustered 0.408–1.038; P =0.084 versus 1). In 2023, the SD of log incidence was 0.355 against 0.821 for log DALY rate, and 2.472 for log years of life lost (YLL) against 0.466 for log years lived with disability (YLD). Country order changed with grouping (Pearson r =0.62): Türkiye’s residual was 0.96 under World Bank Europe and Central Asia, versus −0.22 under GBD North Africa and the Middle East. The 2023 equal-country and population-weighted GDP gaps were 0.445 and 0.103 ( P =0.312). India held 49.1% of the poorest GDP quartile’s population. GBD-derived residuals should not be used as treatment-gap or surgical-access measures.

Background: Auricular cartilage defects, whether congenital or acquired, present a significant reconstructive challenge. Autologous chondrocytes implantation remains the clinical gold standard but is limited by donor-site morbidity, limited cell availability, and dedifferentiation during expansion. Cartilage stem/progenitor cells (CSPCs) have emerged as a promising alternative, yet their comparative properties remain underexplored. Methods: A comprehensive literature review was conducted across PubMed, MEDLINE, Cochrane, and Web of Science databases up to 2026, utilizing keywords such as chondrocytes, chondroprogenitors, Cartilage stem/progenitor cells, CSPCs, auricular cartilage, ear reconstruction and tissue engineering. Results: Chondrocytes exhibit robust matrix synthesis but suffer from dedifferentiation and limited proliferation. CSPCs demonstrate superior self-renewal and immunomodulatory properties, yet face challenges of hypertrophic differentiation and inferior tissue elasticity. Co-culture and scaffold-based strategies have been employed to enhance the functionality of both cell types in engineered constructs. Conclusion: Both chondrocytes and CSPCs present distinct advantages and limitations for auricular cartilage repair. Future strategies should aim to combine their strengths, such as the functional specificity of chondrocytes and the expandability of CSPCs, to develop more effective and clinically feasible tissue-engineered constructs for ear reconstruction.