The metabolic signature of blood lipids: a causal inference study using twins.

Dyslipidemia is one of the cardiometabolic risk factors that influences mortality globally. Unraveling the causality between blood lipids and metabolites and the complex networks connecting lipids, metabolites, and other cardiometabolic traits can help to more accurately reflect the body's metabolic disorders and even cardiometabolic diseases. We conducted targeted metabolomics of 248 metabolites in 437 twins from the Chinese National Twin Registry. Inference about Causation through Examination of FAmiliaL CONfounding (ICE FALCON) analysis was used for causal inference between metabolites and lipid parameters. Bidirectional mediation analysis was performed to explore the linkages between blood lipids, metabolites, and other seven cardiometabolic traits. We identified 44, 1, and 31 metabolites associated with triglyceride (TG), total cholesterol (TC), and high-density lipoprotein-cholesterol (HDL-C), most of which were gut microbiota-derived metabolites. There were 9, 1, and 14 metabolites that showed novel associations with TG, TC, and HDL-C, respectively. ICE FALCON analysis found that TG and HDL-C may have a predicted causal effect on 23 and six metabolites, respectively, and one metabolite may have a predicted causal effect on TG. Mediation analysis discovered 14 linkages connecting blood lipids, metabolites, and other cardiometabolic traits. Our study highlights the significance of gut microbiota-derived metabolites in lipid metabolism. Most of the identified cross-sectional associations may be due to the lipids having a predicted causal effect on metabolites, but not vice versa, nor are they due to family confounding. These findings shed new light on lipid metabolism and personalized management of cardiometabolic diseases.

Lipidomic perturbations of normal-weight adiposity phenotypes and their mediations on diet-adiposity associations.

BACKGROUND & AIMS: Normal-weight obesity (NWO) and normal-weight central obesity (NWCO) have been linked to higher cardiometabolic risks, but their etiological bases and attributable dietary factors remain unclear. In this study we therefore aimed to identify lipidomic signatures and dietary factors related to NWO and NWCO and to explore the mediation associations of lipids in diet-adiposity associations. METHODS: Using a high-coverage targeted lipidomic approach, we quantified 1245 serum lipids in participants with NWO (n = 150), NWCO (n = 150), or propensity-score-matched normal-weight controls (n = 150) based on the Regional Ethnic Cohort Study in Northwest China. Consumption frequency of 28 major food items was recorded using a food frequency questionnaire. RESULTS: Profound lipidomic perturbations of NWCO relative to NWO were observed, and 249 (dominantly glycerolipids) as well as 48 (dominantly glycerophospholipids) lipids were exclusively associated with NWCO or NWO. Based on strong lipidomic signatures identified by a LASSO model, phospholipid biosynthesis was the top enriched pathway of NWCO, and sphingolipid metabolism was the top pathway of NWO. Remarkably, sphingolipids were positively associated with NWO and NWCO, but lyso-phosphatidylcholines were negatively associated with them. Rice, fruit juice, and carbonated drink intakes were positively associated with the risk of NWCO. Both global and individual lipidomic signatures, including SE(28:1_22:6) and HexCer(d18:1/20:1), mediated these diet-NWCO associations (mediation proportion: 15.92%-26.10%). CONCLUSIONS: Differential lipidomic signatures were identified for overall and abdominal adiposity accumulation in normal-weight individuals, underlining their core mediation roles in dietary contributions to adiposity deposition.

Effect of different exercise types on quality of life in patients with breast cancer: A network meta-analysis of randomized controlled trials.

BACKGROUND: Exercise is a rehabilitation strategy for patients with breast cancer; however, the optimal type of exercise remains uncertain. This study aimed to compare the effects of five exercise types on the quality of life of patients with breast cancer and provide a basis for their exercise rehabilitation. METHODS: As of May 2024, we searched four databases: Embase, PubMed, Web of Science, and Cochrane Library, and included randomized controlled trials that analyzed the effect of exercise on the quality of life of patients with breast cancer. A network meta-analysis was performed using a frequency-based framework. RESULTS: Forty-five papers involving 4092 participants were included. The five types of exercises included were all significant in the direct comparison with the control group, except yoga and mind-body exercises. Aerobic, resistance, and combination exercises were associated with quality of life. However, in indirect comparisons, only mind-body exercise versus resistance exercise had a significant effect. The effect of exercise on the quality of life(total health status) of patients with breast cancer was ranked based on surface under the cumulative ranking curve (SUCRA) values combined with effect sizes as follows: aerobic exercise (SUCRA = 84.1) > combined exercise (SUCRA = 78.8) > resistance exercise (SUCRA = 66.4) > yoga (SUCRA = 39.3) > mind-body exercise (SUCRA = 27.2) > usual care (SUCRA = 4.1). CONCLUSIONS: Exercise can rehabilitate the quality of life of patients with breast cancer, and aerobic exercise may be the best type of exercise to improve their quality of life(total health status).

Identification of NETs formation and the renoprotective effect of degraded NETs in lupus nephritis.

To explore molecular biomarkers associated with the pathophysiology and therapy of lupus nephritis (LN), we conducted a joint analysis of transcriptomic data from 40 PBMCs (GSE81622) and 21 kidney samples (GSE112943) from the GEO database using bioinformatics. 976 and 2427 differentially expressed genes (DEGs) were identified in PBMCs and renal tissues. Seven and two functional modules closely related to LN were identified. Further enrichment analysis revealed that the neutrophil activation pathway was highly active in both PBMC and kidney. Subsequently, 16 core genes closely associated with LN were verified by PPI screening and qPCR. In vitro cell models and MRL/lpr mouse models confirmed that the abnormal expression of these core genes was closely linked to neutrophil extracellular traps (NETs) generated by neutrophil activation, while degradation of NETs led to down-regulation of core gene expression, thereby improving pathological symptoms of LN. Therefore, identification of SLE patients exhibiting abnormal expression patterns for these core genes may serve as a useful indicator for kidney involvement. Additionally, targeting neutrophils to modulate their activation levels and inhibit aberrant expression of these genes represents a potential therapeutic strategy for treating LN.

Oral Levodopa Stimulates Copeptin Secretion in Children and Adolescents with Intact Posterior Pituitary Function.

BACKGROUND: Copeptin stimulation tests can be used in the differential diagnosis of polyuria polydipsia syndrome. Current stimulation methods rely on intravenous or subcutaneous administration. Oral stimulus can further simplify the diagnostic approach. The levodopa stimulation test is widely used in the evaluation of growth hormone deficiency (GHD), and the dopamine pathway was reported to be associated with arginine vasopressin secretion. The study aimed to investigate the effect of oral levodopa on copeptin secretion. METHODS: The study was a prospective observational single-center cohort study. Patients < 18 years old with short stature and no symptoms of polyuria or polydipsia undergoing levodopa stimulation test for suspected GHD were recruited from May 2023 to Nov 2023. Copeptin and growth hormone (GH) were measured at 0, 30, 60, 90, and 120min in the levodopa test. The insulin tolerance test with copeptin and GH measured at the same time points was conducted in part of patients. RESULTS: Forty-four participants were included in the final analysis. In the levodopa stimulation test, the median (interquartile range, IQR) copeptin concentration increased from 5.20 (3.51, 8.25) pmol/L to maximum 19.36 (8.97, 108.08) pmol/L (P < 0.001), 3.94 (1.41, 13.88) times of the baseline (P < 0.001). Compared with insulin tolerance test, peak copeptin in the levodopa test was significantly higher (34.61 (13.67, 98.96) vs 8.88 (7.14, 15.42) pmol/L, P = 0.009). Higher copeptin was associated with larger dose of levodopa. CONCLUSIONS: Oral levodopa could be used to stimulate copeptin.

HMGB1 released from pyroptotic vascular endothelial cells promotes immune disorders in exertional heatstroke.

BACKGROUND AND OBJECTIVE: Exertional heatstroke (EHS) mainly occurs in healthy young people with rapid onset and high mortality. EHS immune disorders can cause systemic inflammatory responses and multiple organ failure; however, the underlying mechanisms remain unclear. As high mobility group box 1 (HMGB1) is a prototypical alarmin that activates inflammatory and immune responses, this study aimed to investigate the effect and mechanism of HMGB1 in the pathogenesis of EHS. METHODS: Peripheral blood mononuclear cell (PBMC) transcriptome sequencing of healthy volunteers, classical heatstroke patients, and EHS patients was performed. A mouse model of EHS was established and murine tissue damage was evaluated by H&E staining. HMGB1 localization and release were visualized using immunofluorescence staining. Human umbilical vein endothelial cells (HUVECs) and THP-1 cells were co-cultured to study the effects of HMGB1 on macrophages. A neutralizing anti-HMGB1 antibody was used to evaluate the efficacy of EHS treatment in mice. RESULTS: Plasma and serum HMGB1 levels were significantly increased in EHS patients or mice. EHS-induced endothelial cell pyroptosis promoted HMGB1 release in mice. HMGB1 derived from endothelial cell pyroptosis enhanced macrophage pyroptosis, resulting in immune disorders under EHS conditions. Administration of anti-HMGB1 markedly alleviated tissue injury and systemic inflammatory responses after EHS. CONCLUSIONS: The release of HMGB1 from pyroptotic endothelial cells after EHS promotes pyroptosis of macrophages and systemic inflammatory response, and HMGB1-neutralizing antibody therapy has good application prospects for EHS.

Associations of sleep with cardiometabolic risk factors and cardiovascular diseases: An umbrella review of observational and mendelian randomization studies.

Two researchers independently assessed studies published up to February 5, 2023, across PubMed, Web of Science, Embase, and Cochrane Library, to investigate the associations of sleep traits with cardiometabolic risk factors, as well as with cardiovascular diseases. Fourteen systematic reviews consisting of 23 meta-analyses, and 11 Mendelian randomization (MR) studies were included in this study. Short sleep duration was associated with a higher risk of obesity, type 2 diabetes (T2D), hypertension, stroke, and coronary heart disease (CHD) in observational studies, while a causal role was only demonstrated in obesity, hypertension, and CHD by MR. Similarly, long sleep duration showed connections with a higher risk of obesity, T2D, hypertension, stroke, and CHD in observational studies, none was supported by MR analysis. Both observational and MR studies indicated heightened risks of hypertension, stroke, and CHD in relation to insomnia. Napping was linked to elevated risks of T2D and CHD in observational studies, with MR analysis confirming a causal role in T2D. Additionally, snoring was correlated with increased risks of stroke and CHD in both observational and MR studies. This work consolidates existing evidence on a causal relationship between sleep characteristics and cardiometabolic risk factors, as well as cardiovascular diseases.

Suppressing hydrogen evolution and promoting dendrite free zinc deposition by fluorinated triazine framework towards robust aqueous zinc ion batteries.

Aqueous zinc-ion batteries (AZIBs) have become a research hotspot, but the inevitable zinc dendrites and parasitic reactions in the zinc anode seriously hinder their further development. In this study, three covalent triazine frameworks (DCPY-CTF, CTF-1 and FCTF) have been synthesized and used as artificial protective coatings, in which the fluorinated triazine framework (FCTF) increases the zinc-philic site, thus better promoting dendritic free zinc deposition and inhibiting hydrogen evolution reactions. Excitingly, both experimental results and theoretical calculations indicate that the FCTF interface adjusts the deposition of Zn2+ along the (002) plane, effectively alleviating the formation of zinc dendrites. As expected, Zn@FCTF symmetric cells exhibit cycling stability of over 4000 h (0.25 mA cm-2), meanwhile Zn@FCTF//NHVO full cells provide a high specific capacity of 280 mAh/g at 1.0 A/g, which are superior to those of bare Zn anode. This work provides new insights for suppressing hydrogen evolution and promoting dendrite-free zinc deposition to construct highly stable and reversible AZIBs.

Facile Coordination Transitions in AgCrX2 (X = S, Se): Unprecedented Electrostrain, Negative Piezoelectricity and Thermal Expansion.

The coefficients of piezoelectricity and thermal expansion are generally positive due to the bond anharmonicity. For converse piezoelectricity, the electrostrain obtained in prevalent ceramics is only around 1%. Here we propose that the coordination transition of metal cations may make a paradigm shift. Through first-principles calculations, we predict a series of low-energy phases with distinct coordinations for Ag ions in superionic conductor AgCrX2 (X = S, Se), including ferroelectric and nonpolar phases with distinct interlayer distances. The mobile feature of Ag ions, which can be attributed to its complex coordination chemistry, can facilitate transformation between various coordination phases. Such facile transitions with ultralow barriers can be driven by applying either pressure, an electric field, or a change in temperature, giving rise to various exotic effects, including electrostrain, negative piezoelectricity, and negative thermal expansion. All with unprecedented giant constants, those mechanisms stem from the coordination transitions, distinct from the weak linear effects in previous reports.

CYP8B1 Catalyzes 12alpha-hydroxylation of C27 Bile Acid: In Vitro Conversion of Dihydroxycoprostanic Acid into Trihydroxycoprostanic Acid.

CYP8B1 is the unique P450 enzyme with sterol 12-oxidation activity, playing an exclusive role in 12α-hydroxylating intermediates along the bile acid (BA) synthesis pathway. Despite the long history of BA metabolism studies, it is unclear whether CYP8B1 catalyzes 12α-hydroxylation of C27 BAs, the key intermediates shuttling between mitochondria and peroxisomes. This work provides robust in vitro evidence that both microsomal and recombinant CYP8B1 enzymes catalyze the 12α-hydroxylation of dihydroxycoprostanic acid (DHCA) into trihydroxycoprostanic acid (THCA). On the one hand, DHCA 12α-hydroxylation reactivity is conservatively detected in liver microsomes of both human and preclinical animals. The reactivity of human tissue fractions conforms well with the selectivity of CYP8B1 mRNA expression, while the contribution of P450 enzymes other than CYP8B1 is excluded by reaction phenotyping in commercial recombinant enzymes. On the other hand, we prepared functional recombinant human CYP8B1 proteins according to a recently published protocol. Titration of the purified CYP8B1 proteins with either C4 (7α-hydroxy-4-cholesten-3-one) or DHCA yields expected blue shifts of the heme Soret peak (type I binding). The recombinant CYP8B1 proteins efficiently catalyze 12α-hydroxylation of both DHCA and C4, with Km of 3.0 and 1.9 µM and kcat of 3.2 and 2.6 min-1, respectively. In summary, the confirmed role of CYP8B1 in 12α-hydroxylation of C27 BAs has furnished the forgotten passageway in the BA synthesis pathway. The present finding might have opened a new window to consider the biology of CYP8B1 in glucolipid metabolism and to evaluate CYP8B1 inhibition as a therapeutic approach of crucial interest for metabolic diseases. Significance Statement Academic community has spent about 90 years interpreting the synthesis of bile acids. However, the 12α-hydroxylation of intermediates catalyzed by CYP8B1 is not completely mapped on the classic pathway, particularly for the C27 bile acids, the pivotal intermediates shuttling between mitochondria and peroxisomes. This work discloses the forgotten 12α-hydroxylation pathway from dihydroxycoprostanic acid into trihydroxycoprostanic acid. The present finding may facilitate evaluating CYP8B1 inhibition as a therapeutic approach of crucial interest for metabolic diseases.

Control of paleoclimate and paleoweathering on chromium contents in a non-ultramafic aquifer hosting high chromium groundwater.

Cr(VI) is a carcinogen with proven mutagenic and genotoxic effects. The effects of the depositional environment (e.g., paleoweathering, paleoclimate, and paleoredox condition) on Cr enrichment in non-ultramafic aquifer solids are unclear. In this study, we presented the sedimentary characteristics of a borehole from a typical non-ultramafic aquifer with high Cr groundwater in Jingbian, central Ordos Basin, China. Chromium was enriched in the K1h sandstone aquifer, especially at depths of 400-500 m, with the highest value of mass transport coefficient (τAl,Cr) up to 92.13% and τAl,Fe up to 33.5%. The provenance of aquifer Cr was predominantly intermediate and felsic igneous rocks with a mafic rock mixture. This mafic source was inferred from Cr-rich granodiorite and mafic/ultramafic rocks in the Yinshan (Daqingshan-Wulashan) Block, northern Ordos Basin. The Cr-rich aquifer in K1h was developed due to a moderate chemical index of alteration (CIA) (mean, 56.7) under relatively warm and humid paleoclimate, as evidenced by high CIA-temperature (CIA-Temp) (mean, 6.79 °C) and paleoclimatic index values (mean, 0.40). Fe-Mn redox cycling in the oxic to suboxic environments contributed to aquifer Cr accumulation. Using path analysis, we identified that paleoclimate created favorable weathering conditions and enrichment of Fe contributed to the formation of high-Cr aquifers. The study reveals the formation of positive Cr anomalies in non-ultramafic aquifers, which is the potential source of groundwater Cr, and highlights the effects of depositional factors on Cr accumulation during aquifer deposition or early diagenesis. It can provide new insights into the natural processes of high-Cr sediments occurring in non-ultramafic aquifers.

Gene mutations in newly diagnosed multiple myeloma patients detected by next-generation sequencing technology.

Background: Multiple myeloma (MM) is a heterogeneous plasma-derived hematopoietic malignancy with complex genetic mutation contributing to the pathogenesis. Though gene sequencing has been applied in MM, genetic features from Chinese MM patients are reported less. We investigated the genetic mutation of newly diagnosed multiple myeloma (NDMM) patients and explore its correlation with cytogenetic abnormalities detected by fluorescence in situ hybridization (FISH). Methods: A total of 206 patients with NDMM were enrolled. After enriching plasma cells with CD138 magnetic beads, 92 MM-related target gene mutations were detected by the Illumina sequencing platform, and six common genetic abnormalities were detected by FISH. Results: 162 cases (78.6%) had at least one gene mutation detected by NDMM. The top 5 mutated genes were KRAS, NRAS, TRAF3, BRAF, and TP53. Cytogenetic abnormalities detected by FISH have a certain correlation with gene mutations, t(11;14) translocations are often accompanied by CCND1 and TP53 mutations, KLHL6 in t(4;14), SP140, CDKN1B and PRKD2 in t(14;16) and t(14;20) translocations. The mutation ratio was higher for EGR1, while lower of CCND1 in patients with gain 1q21. The TP53 mutation was more likely in patients with 17p deletion. The gene mutation affects the pathway of the RNA process is more frequently occurring in males and age less than 70 years patients. The International Staging System (ISS) Stage III correlated with gene mutations in the NK-κB pathway while Revised ISS (R-ISS) Stage III correlated with the DNA damage repair pathway. Conclusions: There are various gene mutations in NDMM patients, mainly RAS/MAPK and NF-κB pathway gene pathways.

Multi-omics analysis and the remedial effects of Swertiamarin on hepatic injuries caused by CCl4.

Hepatic diseases pose a significant threat to community health, impacting the quality of life and longevity of millions worldwide. Despite revolutionary advancements in treatment, liver diseases remain a pressing issue, necessitating the development of more effective therapeutic approaches. Here, we conducted a comprehensive multi-omics analysis to investigate the underlying mechanism of Swertiamarin in alleviating hepatic injuries induced by CCl4 in mice. We divided 100 Kunming mice into five groups: RC (control), RM (CCl4), RD (15 mg/Kg Swertiamarin), RZ (30 mg/Kg Swertiamarin), and RG (60 mg/Kg Swertiamarin). Animals in groups RD, RZ, and RG received daily Swertiamarin via gavage, while those in groups RM, RD, RZ, and RG were treated with CCl4 solution intraperitoneally every four days, nine times in total. Our findings revealed that mice in the RM group exhibited slightly lower average weights compared to other groups, along with significantly higher liver weight (p<0.0001) and liver index (p<0.0001). Pathological analysis indicated liver damage characterized by cell degeneration, inflammatory cell infiltration, and hepatic fibrosis in the CCl4-induced group. In contrast, Swertiamarin supplementation mitigated these effects, reducing denatured cells, inflammatory cells, and collagenous fibers in the liver. Serum analysis showed elevated levels of TNF-α (p<0.001), IL-6 (p<0.05), ALT (p<0.001), AST (p<0.0001), MDA (p<0.001), and Hyp (p<0.001) in CCl4-induced animals, along with lower levels of T-AOC (p<0.001), GSH-px (p<0.0001), SOD (p<0.001), and CAT (p<0.01). Microbiome analysis revealed significant differences among groups, with pathogenic taxa such as Arthrinium and Aureobasidium, and probiotic Saccharomyces showing notable variations. Metabolomics analysis identified numerous differentially abundant metabolites, with Swertiamarin-treated animals exhibiting distinct profiles. Our findings highlight the potential of Swertiamarin ameliorating CCl4-induced liver toxicity through modulation of antioxidant capacity, inflammatory response, gut microbiota, and metabolites. These insights may inform the development of novel therapies for liver injury.

Icariside I enhances the effects of immunotherapy in gastrointestinal cancer via targeting TRPV4 and upregulating the cGAS-STING-IFN-I pathway.

Gastrointestinal cancer is among the most common cancers worldwide. Immune checkpoint inhibitor-based cancer immunotherapy has become an innovative approach in cancer treatment; however, its efficacy in gastrointestinal cancer is limited by the absence of infiltration of immune cells within the tumor microenvironment. Therefore, it is therefore urgent to develop a novel therapeutic drug to enhance immunotherapy. In this study, we describe a previously unreported potentiating effect of Icariside I (ICA I, GH01), the main bioactive compound isolated from the Epimedium species, on anti-tumor immune responses. Mechanistically, molecular docking and SPR assay result show that ICA I binding with TRPV4. ICA I induced intracellular Ca2+ increasing and mitochondrial DNA release by targeting TRPV4, which triggered cytosolic ox-mitoDNA release. Importantly, these intracellular ox-mitoDNA fragments were taken up by immune cells in the tumor microenvironment, which amplified the immune response. Moreover, our study shows the remarkable efficacy of sequential administration of ICA I and anti-α-PD-1 mAb in advanced tumors and provides a strong scientific rationale for recommending such a combination therapy for clinical trials. ICA I enhanced the anti-tumor effects with PD-1 inhibitors by regulating the TRPV4/Ca2+/Ox-mitoDNA/cGAS/STING axis. We expect that these findings will be translated into clinical therapies, which will benefit more patients with cancer in the near future.

R2-ISS staging combined with circulating plasma cells improves risk stratification for newly diagnosed multiple myeloma: a single-center real-world study.

We aimed to evaluate if circulating plasma cells (CPC) detected by flow cytometry could add prognostic value of R2-ISS staging. We collected the electronic medical records of 336 newly diagnosed MM patients (NDMM) in our hospital from January 2017 to June 2023. The median overall survival (OS) for patients and R2-ISS stage I-IV were not reached (NR), NR, 58 months and 53 months, respectively. There was no significant difference in OS between patients with stage I and patients with stage II (P = 0.309) or between patients with stage III and patients with stage IV (P = 0.391). All the cases were re-classified according to R2-ISS stage and CPC numbers ≥ 0.05% (CPC high) or<0.05% (CPC low) into four new risk groups: Group 1: R2-ISS stage I + R2-ISS stage II and CPC low, Group 2: R2-ISS stage II and CPC high + R2-ISS stage III and CPC low, Group 3: R2-ISS stage III and CPC high + R2-ISS stage IV and CPC low, Group 4: R2-ISS stage IV and CPC high. The median OS were NR, NR, 57 months and 32 months. OS of Group 1 was significantly longer than that of Group 2 (P = 0.033). OS in Group 2 was significantly longer than that of Group 3 (P = 0.007). OS in Group 3 was significantly longer than that of Group 4 (P = 0.041). R2-ISS staging combined with CPC can improve risk stratification for NDMM patients.

Gut microbiota, a key to understanding the knowledge gaps on micro-nanoplastics-related biological effects and biodegradation.

Micro-nanoplastics (MNPs) pollution as a global environmental issue has received increasing interest in recent years. MNPs can enter and accumulate in the organisms including human beings mainly via ingestion and inhalation, and large amounts of foodborne MNPs have been frequently detected in human intestinal tracts and fecal samples. MNPs regulate the structure composition and metabolic functions of gut microbiota, which may cause the imbalance of intestinal ecosystems of the hosts and further mediate the occurrence and development of various diseases. In addition, a growing number of MNPs-degrading strains have been isolated from organismal feces. MNPs-degraders colonize the plastic surfaces and form the biofilms, and the long-chain polymers of MNPs can be biologically depolymerized into short chains. In general, MNPs are gradually degraded into small molecule substances (e.g., N2, CH4, H2O, and CO2) via a series of enzymatic catalyses, mainly including biodeterioration, fragmentation, assimilation, and mineralization. In this review, we outline the current progress of MNPs effects on gut microbiota and MNPs degradation by gut microbiota, which provide a certain theoretical basis for fully understanding the knowledge gaps on MNPs-related biological effect and biodegradation.

Shared genetic basis connects smoking behaviors and bone health: insights from a genome-wide cross-trait analysis.

Although the negative association of tobacco smoking with osteoporosis is well-documented, little is known regarding the shared genetic basis underlying these conditions. In this study, we aim to investigate a shared genetic architecture between smoking and heel estimated bone mineral density (eBMD), a reliable proxy for osteoporosis. We conducted a comprehensive genome-wide cross-trait analysis to identify genetic correlation, pleiotropic loci and causal relationship of smoking with eBMD, leveraging summary statistics of the hitherto largest genome-wide association studies conducted in European ancestry for smoking initiation (Nsmoker = 1 175 108, Nnonsmoker = 1 493 921), heaviness (cigarettes per day, N = 618 489), cessation (Ncurrent smoker = 304 244, Nformer smoker = 843 028), and eBMD (N = 426 824). A significant negative global genetic correlation was found for smoking cessation and eBMD (${r}_g$ = -0.051, P = 0.01), while we failed to identify a significant global genetic correlation of smoking initiation or heaviness with eBMD. Partitioning the whole genome into independent blocks, we observed 6 significant shared local signals for smoking and eBMD, with 22q13.1 showing the strongest regional genetic correlation. Such a genetic overlap was further supported by 71 pleiotropic loci identified in the cross-trait meta-analysis. Mendelian randomization identified no causal effect of smoking initiation (beta = -0.003 g/cm2, 95% CI = -0.033 to 0.027) or heaviness (beta = -0.017 g/cm2, 95% CI = -0.072 to 0.038) on eBMD, but a putative causal effect of genetic predisposition to being a current smoker was associated with a lower eBMD compared to former smokers (beta = -0.100 g/cm2, 95% CI = -0.181 to -0.018). Our study demonstrates a pronounced biological pleiotropy as well as a putative causal link between current smoking status and eBMD, providing novel insights into the primary prevention and modifiable intervention of osteoporosis by advocating individuals to avoid, reduce or quit smoking as early as possible.

We conducted a comprehensive genome-wide cross-trait analysis to investigate the shared genetic basis and causal relationship underlying smoking and osteoporosis. Our findings revealed that smoking and eBMD are inherently linked through biological pleiotropy. Importantly, our study discovered that quitting smoking significantly reduced the risk of lower eBMD. We recommend individuals to avoid, reduce, or quit smoking as early as possible to protect bone health.