Cardiovascular-kidney-metabolic (CKM) syndrome is an
emerging concept that emphasizes the interconnected pathophysiology
of cardiovascular disease (CVD), chronic kidney disease (CKD), and
metabolic disorders (1). The
2023 scientific statement from the American Heart Association
formally defines and stages CKM syndrome, enabling a more
integrated approach to these coexisting conditions (2). CKM has major public health
implications: Recent data show nearly half of U.S. adults aged ≥20
years have some form of CVD, and 43.6% of deaths in patients with
end-stage renal disease (ESRD) are due to cardiovascular causes
(3). These statistics underscore
the need for comprehensive strategies that simultaneously target
cardiac, renal, and metabolic dysfunction.
Research increasingly recognizes sex as a key factor
influencing CKM syndrome. Men and women differ markedly in the
incidence, progression, and outcomes of CVD, CKD, and metabolic
diseases (1). These disparities
stem in part from sex hormones and their effects on physiological
pathways, such as the renin-angiotensin-aldosterone system (RAAS),
oxidative stress, inflammation, endothelial function, and insulin
sensitivity (4). For example,
premenopausal women have a lower incidence of CVD than age-matched
men, yet when severe cardiovascular events occur, women often
experience higher mortality and worse outcomes (5). A similar pattern exists in CKD:
Women have higher reported CKD prevalence, but men predominate in
ESRD and dialysis (6). A large
30-year U.S. cohort (1988-2018) of 33,868 adults found that
although women were less likely than men to progress to advanced
CKM stages, their mortality risk was higher at each level of
severity (7). These findings
suggest that biological sex-related healthcare factors may jointly
shape CKM trajectories. These observations highlight the urgent
need to elucidate sex-specific mechanisms and translate this
knowledge into interventions that reduce sex disparities in
multisystem disease risk (8-10).
In summary, recognizing sex differences in CKM
syndrome has important clinical significance. In the present
review, current knowledge on sex-specific mechanisms of CKM
pathogenesis, clinical trajectories, and pharmacologic responses
are synthesized. Consistencies and gaps between basic science and
clinical observations are examined, and future directions for
sex-stratified prevention and treatment are outlined.
Sex steroids have profound effects on
cardiovascular, renal, and metabolic physiology (11-17). Estrogen generally exerts
protective effects on the heart-kidney axis, whereas androgens tend
to promote pathological changes (14-17). Acting through estrogen receptors
ERα/ERβ, estrogen downregulates renin, angiotensin-converting
enzyme (ACE), and angiotensin II receptors, thereby suppressing
RAAS activity (18-20). By contrast, testosterone tends to
amplify RAAS signaling, which may partly explain the higher
susceptibility of men to hypertension and renal damage (21,22). Estrogen also promotes endothelial
nitric oxide production and reduces oxidative stress in tissues
(23-25), whereas androgens enhance
vasoconstriction and oxidative injury (21,26-28). These hormone-driven effects on
vasomotor tone and inflammation contribute to sex differences in
vascular and renal health.
The vascular endothelium is crucial for
cardiovascular health and is strongly influenced by sex (45). Premenopausal women typically have
superior endothelial function compared with men of the same age,
with higher baseline nitric oxide release and vasodilatory tone
(46). Estrogen contributes to
this advantage by enhancing endothelial nitric oxide synthase
activity and inhibiting vascular smooth muscle proliferation
(27). By contrast, androgens
elevate vasoconstrictors such as endothelin-1, leading to higher
vascular tone in men (28).
These differences change with age: After menopause, declining
estrogen causes endothelium-dependent dilation to deteriorate and
arterial compliance to worsen more rapidly in women (47,48). The antioxidant properties of
estrogen help preserve endothelial function, whereas androgen
excess exacerbates oxidative injury (49-51). The superior endothelial health of
premenopausal women helps delay cardiovascular events during
reproductive years, but this advantage erodes after menopause,
contributing to the rising cardiovascular risk in older women.
On a larger scale, arterial aging follows
sex-specific patterns. Premenopausal women have more compliant
large arteries and lower arterial stiffness than men, largely due
to estrogen-mediated reduction of collagen deposition and
enhancement of endothelial nitric oxide (52). After menopause, arterial
stiffness in women accelerates rapidly and can equal or exceed that
of men (48). This late-life
increase in stiffness raises systolic and pulse pressures,
predisposing women to isolated systolic hypertension and heart
failure (HF) with preserved ejection fraction (HFpEF). A membrane
estrogen receptor, G protein-coupled estrogen receptor 1 (GPER1),
has been shown to promote nitric oxide release and natriuresis,
effects that may contribute to female-specific cardiovascular
protection and are attenuated in men (53,54). Overall, men experience greater
arterial stiffening earlier in life, whereas women undergo a
steeper increase after menopause. These two distinct trajectories
link macrovascular dysfunction to sex-specific CKM outcomes.
Male and female kidneys differ anatomically and
functionally. On average, men have larger kidneys and slightly
higher glomerular filtration rates (GFR) in young adulthood
(55). However, women appear to
have some inherent protection. Despite a higher reported prevalence
of early-stage CKD in women (56), men are more likely to progress to
ESRD and dialysis (57). This
suggests that renal function in men may deteriorate faster, or that
clinical interventions differ by sex. Biological factors likely
contribute, as male kidneys appear more prone to persistent
low-grade inflammation and fibrosis (39).
Hemodynamic sensitivity further differs by sex:
Kidneys in men were shown to exhibit higher salt sensitivity and
stronger RAAS activation, making hypertension more damaging
(64,65). By contrast, kidneys in women were
reported to be relatively shielded by estrogen-modulated RAAS,
showing less salt- and pressure-induced injury (66,67). In summary, estrogen has been
demonstrated to provide females with renal protection (slower
fibrosis and preserved tubular function), whereas men were shown to
be predisposed to accelerated nephron loss and decline. These
mechanisms help explain why male patients with CKD tend to progress
more rapidly and suffer worse outcomes.
Emerging biomarkers reflect these risks. For
example, soluble urokinase plasminogen activator receptor (suPAR),
an inflammatory marker linked to cardiorenal risk, was reported to
be ~10% higher in women than men (68). Elevated suPAR was shown to
predict adverse cardiovascular and renal outcomes in both sexes,
but using sex-specific cutoffs may improve risk stratification
(69,70).
Sex differences in cardiac remodeling and HF
phenotypes are well documented. Men tend to develop ventricular
dilation and systolic dysfunction in response to overload or
injury, whereas women more often develop concentric hypertrophy and
diastolic dysfunction with preserved ejection fraction (71-75). Clinically, this manifests as men
more frequently presenting with HF with reduced ejection fraction
(HFrEF), often due to ischemic heart disease, while women more
commonly develop HFpEF linked to hypertension and obesity (74,75).
On a cellular level, pressure overload was shown to
trigger different adaptations: Female hearts were reported to
respond with concentric hypertrophy (wall thickening and increased
stiffness) that can lead to diastolic dysfunction, whereas male
hearts were shown to undergo eccentric hypertrophy (chamber
dilation) and a greater decline in systolic function (76,77). Estrogen has been demonstrated to
exert anti-fibrotic effects on cardiac fibroblasts, protecting
premenopausal women; by contrast, men and postmenopausal women
(with low estrogen) were reported to show more fibrotic remodeling
(77). Female myocardium was
also revealed to maintain more efficient energy metabolism under
stress (78), which helps
preserve function during ischemic or metabolic insults.
In terms of outcomes, women with chronic HF have
lower mortality and fewer sudden deaths than men (79). This survival advantage may
reflect later onset age in women, fewer ischemic triggers, and
estrogenic protection. For instance, in ischemia-reperfusion
models, estrogen was shown to improve coronary collateral
circulation and reduce infarct size, whereas androgens were
revealed to exacerbate cardiomyocyte apoptosis and impair repair
(80-83). Certain cardiomyopathies further
highlight sex effects: Stress-induced ('Takotsubo') cardiomyopathy
and peripartum cardiomyopathy occur almost exclusively in women
(84,85).
In summary, the female heart remodels distinctly,
tending toward concentric hypertrophy and stiffness while
preserving systolic function, whereas the male heart dilates and
loses contractile reserve. Notably, after myocardial infarction
women often exhibit higher levels of fibrotic biomarkers (such as
galectin-3) than men, correlating with greater hypertrophy and HF
(86,87). This suggests that when injured,
female hearts may engage profibrotic pathways more readily,
illustrating the complex and sometimes paradoxical nature of sex
differences in cardiac adaptation.
Sex also shapes metabolic profiles relevant to CKM
risk. Menopause triggers adverse lipid changes in women:
Low-density lipoprotein (LDL) cholesterol rises and high-density
lipoprotein cholesterol falls after estrogen loss, which may erode
atherosclerosis protection in women (88). A life-course study found that the
lipid-related cardiovascular risk in women is lower than that in
men only during premenopausal ages; in childhood and after ~50
years of age, lipid profiles in women are more atherogenic than
those in men (89). By contrast,
men often have higher triglycerides, more small dense LDL
particles, and greater visceral fat, all of which increase
atherosclerotic risk in middle age (90,91).
Sex differences also extend to glucose and insulin
metabolism. Women generally have slightly higher insulin
sensitivity and stronger pancreatic β-cell insulin secretion than
men (92-94). Consequently, men develop insulin
resistance and type 2 diabetes (T2D) at lower body mass indices,
whereas women are often diagnosed later and at higher BMI (95). Unique female stressors increase
diabetes risk: A history of gestational diabetes is a major
predictor of later T2D in women (96), and menopause can unmask latent
insulin resistance (97). Men
also tend to accumulate visceral fat, whereas premenopausal women
usually store more subcutaneous fat (98). Visceral fat promotes inflammation
and insulin resistance, thus men with obesity face higher metabolic
risk. After menopause, fat in women redistributes toward visceral
depots and risk climbs rapidly (99,100).
Sex differences persist once diabetes is
established. Diabetes effectively eliminates the baseline
cardiovascular advantage of women: Diabetic women suffer a
disproportionately larger relative increase in coronary and stroke
risk than diabetic men (101-103). For example, several studies
found diabetic women have an ~27% higher stroke risk than diabetic
men (102,103). Conversely, men with diabetes
are more prone to microvascular complications: They have higher
rates of diabetic kidney disease, retinopathy, and neuropathy than
women (104). Clinically,
diabetic men often have greater proteinuria, faster progression to
dialysis, and more severe retinopathy or limb amputations. These
disparities may reflect androgen-driven inflammation and behavioral
factors such as poorer glycemic control and higher smoking rates in
men (93). There is also
evidence that women with diabetes may receive less aggressive
cardiovascular preventive care than men (102).
Underlying these outcomes, emerging mediators are
being identified. For instance, circulating proprotein convertase
subtilisin/kexin type 9 (PCSK9), which degrades LDL receptors, is
higher in women than in men, and rises further after menopause
(105). This
estrogen-associated PCSK9 increase may partly explain the
disproportionate LDL elevation and atherosclerotic risk women
experience post-menopause (106).
In summary, baseline sex differences in lipid and
glucose metabolism create distinct vulnerabilities: Men have a
smaller 'metabolic reserve' and develop dyslipidemia and insulin
resistance at earlier stages, while premenopausal women benefit
from estrogen-mediated protection but then suffer a sharper risk
rise after menopause. These metabolic factors contribute to the
sex-specific patterns of CKM-related disease (Fig. 1).
Sex differences profoundly affect clinical CKM
outcomes. Men have a significantly higher risk of coronary artery
disease and myocardial infarction in early and mid-adulthood than
women (107,108). Cardiovascular events in
premenopausal women are typically delayed by roughly a decade due
to estrogen-mediated protective effects (107,108). Over the lifespan, men and women
were shown to have similar overall HF risk, but the subtypes
differ: Men more often develop HFrEF (usually ischemic), while
women more often develop HFpEF (often linked to hypertension and
obesity) (74,75).
Men were shown to have a higher incidence of acute
cardiovascular events, including sudden cardiac death and
life-threatening arrhythmias, and were revealed to be more likely
to present in midlife with acute coronary syndromes or abrupt HF.
By contrast, women more often develop chronic HF at older ages,
typically on a background of long-standing hypertension and
metabolic disease. When a major event such as myocardial infarction
occurs, women frequently experience worse short-term outcomes with
higher in-hospital mortality, likely reflecting older age, greater
comorbidity burden, delays in recognition, and biological
differences in response (109,110).
CKD epidemiology also shows sex patterns. Women
report slightly higher CKD prevalence in the general population,
likely reflecting greater longevity in women (111). However, men progress to
advanced CKD and require dialysis more often than women (112). In fact, men outnumber women in
dialysis programs worldwide despite similar overall CKD burden
(113). Possible explanations
include faster biological progression in men (greater
fibrosis/inflammation) (39),
lower competing mortality in men, and healthcare factors such as
differences in referral timing and access to kidney replacement
therapy. Because these access-related issues are influenced by sex,
they should be interpreted as sex-related disparities rather than
purely biological differences. Notably, even after adjusting for
age and comorbidities, female patients with ESRD were reported to
have lower access to dialysis than male patients (114, 115), suggesting sex disparities in
CKD management.
Clinically, male patients with CKD often present
with higher proteinuria and faster GFR decline, whereas women may
linger at moderate CKD stages. Nonetheless, clinicians should be
vigilant about risk in women after menopause, when protective
factors in women decline (111). In practice, this means applying
aggressive CKD monitoring and intervention in men to delay
progression, while ensuring timely nephrology referral in women to
avoid sex-based treatment delays (116).
Sex differences are amplified in diabetes outcomes
and have practical implications for CKM management. In women,
diabetes substantially attenuates the premenopausal cardiovascular
advantage and is associated with a higher relative burden of
cardiovascular complications. Therefore, cardiovascular risk
assessment, lipid-lowering therapy, blood pressure control and
early screening for coronary and cerebrovascular disease should be
emphasized in women with diabetes. In men, diabetes is more
frequently accompanied by microvascular complications, including
diabetic kidney disease, retinopathy and neuropathy, supporting
closer surveillance of albuminuria, renal function, retinal disease
and peripheral vascular complications. These clinical patterns
indicate that diabetes care in CKM syndrome should incorporate
sex-sensitive risk assessment rather than applying a uniform
monitoring strategy to all patients (Fig. 2) (93,102).
Sexual dysfunction is an underrecognized marker of
CKM risk. In men, erectile dysfunction (ED) reflects systemic
endothelial dysfunction and strongly predicts cardiovascular events
and mortality (men with ED have roughly 40% higher CVD risk)
(118). In women, sexual
dysfunction (reduced arousal, lubrication, orgasm) was reported to
be associated with hypertension, diabetes, and metabolic syndrome,
suggesting genital and systemic vascular impairment (119). Clinically, the presence of ED
should prompt aggressive cardiovascular risk management, and
healthcare providers should inquire about sexual health in women as
it may identify high-risk patients (120). Treating sexual dysfunction was
shown to improve quality of life and may enhance adherence to
cardiometabolic therapies (121). In summary, sexual dysfunction
signals underlying vascular disease and warrants a comprehensive,
sex-sensitive prevention and care approach.
Sex differences influence not only disease
mechanisms but also treatment responses and side effects. In CKM
syndrome, therapies such as lipid-lowering agents,
antihypertensives, and glucose-lowering drugs may have sex-specific
nuances (Fig. 3 and Table I). Therefore, the following
section emphasizes reported trends, limitations of subgroup
analyses, and the need to avoid overinterpreting sex-specific
treatment effects when robust interaction testing is
unavailable.
Statins are the cornerstone of atherosclerotic
cardiovascular disease prevention, lowering LDL cholesterol and
reducing events in both sexes (122). Yet a treatment gap exists:
Eligible women are less likely than men to be prescribed statins
(especially high-intensity regimens), receive adequate counseling,
or continue therapy (often discontinuing due to side-effect
concerns) (123). LDL lowering
efficacy is substantial in both sexes, but women often receive
lower doses and achieve target LDL less frequently (124). Notably, pooled trials show no
significant sex interaction in statin benefit for primary or
secondary prevention (125,126). Women may report myalgia,
fatigue or concerns about adverse effects slightly more often in
some studies, and statin-associated new-onset diabetes has also
been reported, but these findings do not negate the overall
cardiovascular benefit. Closing the gap in statin initiation,
dosing, and adherence for women is essential to ensure they receive
equal preventable benefit (124-126).
RAAS inhibitors [ACE inhibitors (ACEI), angiotensin
receptor blockers (ARBs), and mineralocorticoid receptor
antagonists] are foundational for hypertension, HF, and proteinuric
CKD (127). Both men and women
benefit from blood pressure (BP) reduction and improved outcomes
with these drugs, but some sex differences emerge. Some studies
suggest that men may achieve slightly greater BP reduction or
outcome improvement with ACEI, whereas women may have at least
comparable responses to ARBs; however, the evidence is
heterogeneous and does not support a universal sex-based hierarchy
of RAAS inhibitor choice (128-131). Women also appear to be more
sensitive to mineralocorticoid antagonists, seeing larger BP and
left ventricular mass reductions with these agents (65). ACEI cause cough and angioedema
more often in women, so early switch to an ARB is reasonable when
intolerance arises (128).
Pharmacologically, women reach effective RAAS blockade at lower ARB
doses and may have greater BP lowering with combinations (such as
valsartan plus amlodipine) (132-135). Long-term outcome data are
mixed: Some evidence suggests stronger mortality reduction with
ACEI in men, while ARBs and angiotensin receptor-neprilysin
inhibitors may provide relatively greater benefit in women
(especially with HFpEF) (136-138). In practice, RAAS blockade
should be individualized according to indication, renal function,
potassium level, BP, tolerability and comorbidity profile; sex may
inform monitoring and adverse-effect vigilance but should not
replace guideline-directed indications.
SGLT2 inhibitors deliver robust cardiorenal
protection across diabetes, HF, and CKD, significantly reducing
major adverse cardiovascular events (MACE), HF hospitalizations,
and CKD progression in large trials (139-141). Analyses of sex differences have
been mixed: One meta-analysis found significant MACE reduction in
men but only borderline in women (likely reflecting fewer women in
trials and lower baseline risk), while other analyses reported no
sex interaction for cardiovascular death or HF outcomes (142-144). Dedicated HF and CKD trials show
similar relative risk reductions for men and women (145,146). Adverse events do show sex
patterns: Genital mycotic infections are more common in women
(usually mild and treatable), men should be counseled about the
very rare risk of Fournier's gangrene, and older women may be more
prone to volume depletion (147-149). Overall, current evidence
supports the use of SGLT2 inhibitors in eligible patients of both
sexes, while emphasizing sex-aware counseling on genital
infections, hydration and early symptom management. Ongoing
research with greater female representation will further clarify
any residual sex-specific effects (150).
GLP-1RAs (such as liraglutide and semaglutide)
improve glycemia, promote weight loss, and reduce cardiovascular
and renal risk in CKM syndrome (151). Major outcome trials (LEADER and
SUSTAIN-6) and meta-analyses show substantial benefits in both
sexes with no consistent sex-related differences in efficacy
(152). Some real-world
research suggests that women may derive slightly greater
cardiovascular or weight-loss benefit from GLP-1RAs, but these
observations remain exploratory and may reflect differences in body
weight, adherence, baseline risk or treatment selection. In
practice, sex-based differences in GLP-1RA effects are not
sufficiently robust to mandate different prescribing; these drugs
should be used in all eligible patients while further research
explores hormonal, genetic and pharmacokinetic modifiers (153).
Lifestyle changes and glucose-lowering therapies are
essential for both sexes, but sex differences shape insulin
resistance and treatment patterns (154-156). Men display significantly higher
baseline insulin resistance and experience greater improvements in
fasting insulin and homeostatic model assessment of insulin
resistance for a given weight loss compared with women (154,157). Most oral glycemic agents are
equally effective in men and women, and GLP-1 agonists have been
shown to reduce cardiovascular events similarly across sexes
(158,159). Insulin therapy itself achieves
comparable glycemic control, but women often delay its initiation
due to concerns about weight gain and hypoglycemia (160). Women generally have lower body
weight and thus require lower insulin doses; some data suggest
women may experience hypoglycemia slightly more often. In addition,
younger women have been shown to receive statins and other
cardioprotective therapies less frequently than men, indicating
gaps in comprehensive care (93). Polycystic ovary syndrome (PCOS),
a hyperandrogenic condition in women, exemplifies these sex hormone
effects: Women with PCOS have pronounced insulin resistance and
metabolic syndrome, with concurrent dyslipidemia and early vascular
dysfunction (161). This
confers markedly higher cardiovascular risk. A recent systematic
review and meta-analysis reported significantly elevated rates of
myocardial infarction and stroke in PCOS (162). PCOS pathophysiology
(androgen-driven insulin resistance) parallels male metabolic
profiles, making it a human model to study sex differences in CKM
outcomes. PCOS may also increase chronic kidney disease risk
through systemic inflammation and metabolic stress (163). Clinically, these insights
suggest a tailored approach: Men may benefit from early and
intensive weight-loss strategies to reduce insulin resistance,
whereas women may require proactive counseling to avoid unnecessary
delay in insulin or combination therapy and to support hypoglycemia
prevention. In women, cardiovascular risk management should also be
intensified and education regarding self-monitoring and
hypoglycemia prevention should be emphasized, especially in older
age (164).
Sex shapes pharmacokinetic/pharmacodynamic (PK/PD)
profiles through coordinated effects on drug-metabolizing enzymes,
transporters, targets, and immune tone (165-168). In aggregate, women exhibit
higher hepatic CYP3A4 activity, whereas men tend to show higher
CYP2D6, CYP2C19, CYP2E1, and CYP1A2 activity (166,167). Sex steroids further modulate
these pathways and this regulation extends to transporters and
receptors (167). Genetic
polymorphisms in key enzymes such as CYP3A5 and CYP2C9 intersect
with sex effects, and sex-linked expression of drug targets may
shape treatment response (168). Females generally mount stronger
innate and adaptive immune responses (169), which can influence efficacy and
tolerability.
Population-PK showed no clinically meaningful sex
effect for dapagliflozin exposure (175). Genital mycotic infections were
reported to be more frequent in women (176). Cardio-renal outcome benefits
were shown to be comparable in women and men and PDs appeared to be
similar when normalized to urinary creatinine (177,178).
Liraglutide exposure was shown to be 30-32% higher
in females at similar body weight and this finding was replicated
in population-PK meta-analyses (179-181). However, exposure-response
analyses do not currently support routine sex-specific liraglutide
dose adjustment. Trials and real-world data often show similar or
greater weight loss in women and possibly greater cardiovascular
protection in women, without a sex-specific safety signal (182-184).
Women were reported to experience metformin-related
gastrointestinal intolerance more often (185,186). Insulin sensitivity has been
shown to vary across the menstrual cycle and is typically lower in
the luteal phase, supporting individualized titration in some women
(187,188).
Collectively, current data rarely mandate routine
sex-specific dosing. They do support explicit consideration of sex,
genotype, and hormonal status when selecting and titrating therapy.
Future trials should prespecify sex-stratified PK/PD and clinical
outcome analyses to determine when observed sex differences are
actionable rather than merely associative.
To advance precise and equitable care in CKM
syndrome, future efforts should systematically treat sex as a
biological variable across research and practice. Large clinical
trials need balanced enrollment of men and women, prespecified sex
and menopausal status, and routine reporting of outcomes by sex to
generate evidence for guidelines. At the same time, sex-related
determinants such as access to care, referral timing, adherence,
socioeconomic status, and underrepresentation in clinical trials
should be evaluated separately from biological sex. Professional
societies should codify sex specific recommendations such as
prioritizing intensive cardiovascular risk management for diabetic
women, ensuring closer CKD surveillance for men, and substituting
ARBs when ACEI cause cough in women. Precision prescribing should
evaluate sex appropriate dosing and therapy choices, including
whether women benefit from lower doses of RAAS inhibitors or
require different glucose lowering strategies, and targeted
interventions such as early low dose estrogen at menopause should
be tested in sex specific trials to assess safety and efficacy.
Translational research should leverage single cell and other omics
to identify sex biased molecular targets and should test
interventions in both sexes under physiological hormone conditions,
enabling development of selective receptor modulators or tissue
specific therapies. Finally, greater awareness among clinicians and
patients about sex specific risks and responses can improve
prevention and adherence and support personalized management.
Together these strategies aim to narrow outcome disparities and
move the field toward sex-informed precision medicine in
cardiorenal metabolic health.
Sex differences in CKM syndrome are complex but
critically important. They span from fundamental biological
mechanisms to clinical outcomes and therapeutic responses. Ongoing
interdisciplinary research and collaboration are essential to
realize sex-stratified precision medicine in CKM disease. By
tailoring prevention and treatment to the unique needs of men and
women, outcomes can be improved and truly personalized, equitable
healthcare can be advanced.
Not applicable.
HH and JC designed the scope and structure of the
review. HH, JC and YF performed structured literature searches. HH
and JC critically synthesized and interpreted the findings. HH and
JC wrote the original draft. YF and HH revised major sections of
the manuscript. All authors read and approved the final manuscript.
Data authentication is not applicable.
Not applicable.
Not applicable.
The authors declare that they have no competing
interests.
Not applicable.
This work was funded by grants from the National Natural Science
Foundation of China (grant nos. 82100705 and 82201515).
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