Background: The marked clinical and pathophysiological heterogeneity of HFpEF has repeatedly undermined uniform treatment strategies. Consequently, identifying distinct phenotypes and medication-associated patterns across phenotypes may inform future precision-medicine research. Methods: In this multicohort retrospective study, patients with HFpEF were included from MIMIC-IV (derivation cohort, n = 2,511), the MIMIC-III CareVue subset (internal validation cohort, n = 1,524), and the Second Hospital of Hebei Medical University (external application cohort, n = 340). Unsupervised K-prototypes clustering was used to derive phenotypic groups, with K = 2 evaluated as a lower-resolution sensitivity solution. All phenotype-stratified medication analyses were exploratory. In the derivation and internal validation cohorts, overlap weighting was the primary weighted analysis and stabilized inverse probability of treatment weighting was a sensitivity analysis; external medication estimates were reported descriptively because adequate within-group covariate balance was not achieved. A TabPFN phenotype-assignment classifier was developed after recursive feature elimination, evaluated in internal validation against independently reclustered labels aligned by prespecified one-to-one Hungarian assignment on cluster-profile distances, and applied without refitting in the external cohort. Results: The primary three-cluster solution identified clinically interpretable but partially overlapping cardiorenal-metabolic, hypertensive-pulmonary, and low-blood-pressure/arrhythmia profiles. K = 2 had a higher mean silhouette width than K = 3 (0.083 versus 0.060), whereas both solutions showed high median resampling stability (ARI, 0.940 versus 0.924). A graded 365-day mortality difference was observed across the three clusters in the derivation cohort, but between-cluster survival differences were not statistically significant in the internal validation or external application cohorts. In the derivation and internal validation cohorts, no weighted cluster-specific medication association remained statistically significant after FDR correction, and all medication-by-cluster interaction tests were nonsignificant. External medication estimates were descriptive and were not used for confirmatory inference. The fixed TabPFN classifier achieved one-versus-rest AUCs of 0.951–0.969 in internal validation (10-bin multiclass ECE = 0.028). Conclusion: Routinely collected ICU data supported an exploratory framework for describing overlapping HFpEF phenotypes and reproducibly assigning machine-derived labels. The analyses did not establish phenotype-specific medication effects, and the classifier should be regarded as a research tool pending prospective multicenter validation.

Background: Polystyrene nanoplastics (PS-NPs) are emerging contaminants that may pose a risk to human kidney health. This study investigated whether endoplasmic reticulum stress (ERS) contributes to PS-NP-induced kidney injury and explored the potential role of hydrogen sulfide (H₂S) in the underlying mechanism. Methods: Kidney dysfunction, fibrosis, ERS, oxidative stress, Cu/Zn superoxide dismutase (SOD) activity, cystathionine-γ-lyase (CSE) expression, and plasma H₂S levels were assessed following 4 weeks of PS-NPs exposure. The effects of the ATF6 inhibitor melatonin and exogenous H₂S supplementation were also evaluated. Using a Biacore SPR system, experiments were performed to investigate the interaction between PS-NPs and Cu/Zn SOD and to determine whether H₂S affects this interaction. Results: PS-NPs exposure induced kidney dysfunction and fibrosis and increased the expression of activating transcription factor 6 (ATF6) and glucose-regulated protein 78 (GRP78) levels. Treatment with melatonin alleviated PS-NPs-induced kidney dysfunction and fibrosis. PS-NPs also aggravated renal oxidative stress by inhibiting Cu/Zn SOD activity, while reducing renal CSE expression and plasma H₂S levels. Exogenous H₂S supplementation attenuated renal oxidative stress, reduced ERS, and subsequently ameliorated kidney dysfunction and fibrosis. In vitro, PS-NPs directly bound to Cu/Zn SOD and decreased its enzymatic activity. H₂S restored Cu/Zn SOD activity by interfering with the interaction between PS-NPs and Cu/Zn SOD. Conclusions: H₂S alleviates PS-NP-induced kidney dysfunction and fibrosis by restoring Cu/Zn SOD activity, thereby reducing the activation of the ATF6-GRP78 pathway. These findings identify the H₂S/Cu/Zn SOD axis as a potential mechanism underlying PS-NP-induced kidney injury and as a possible therapeutic target.