Ischemic stroke is a leading cause of global mortality and long-term disability, with limited therapeutic options. Increasing evidence from experimental studies suggests that fibroblast growth factors (FGFs) play important roles in regulating key biological processes involved in brain repair following ischemia. This review examines the existing evidence to understand the functional roles of FGFs in ischemic stroke, highlighting findings from in vivo and in vitro models, as well as outcomes from clinical investigations. FGFs contribute to neuroprotection by supporting neuronal survival, modulating inflammatory responses, preserving blood-brain barrier (BBB) integrity, and enhancing angiogenesis. Despite promising data from experimental models, clinical translation of FGF-based therapies has proven challenging. Clinical trials have encountered issues such as safety concerns, particularly regarding optimal dosing and the risk of adverse effects, which complicates treatment response. These limitations highlight the complexity of translating FGF-based therapies into clinical practice in stroke treatment. Additionally, emerging FGF biomarkers may help predict therapeutic responses and guide patient selection and diagnosis. Future research should focus on optimizing delivery systems, identifying therapeutic windows, and improving clinical trial design, as successful clinical translation of FGF therapies relies on resolving subtype-specificity and refining delivery strategies to ensure targeted and effective treatment. Therefore, gaining a deeper understanding of the timing and context of FGF activity following ischemic stroke could pave the way for successful clinical applications, such as early neuroprotection, preservation of BBB integrity, and reduction of neuroinflammation. This understanding could also support the development of more targeted and effective interventions for ischemic stroke.

Diabetic stroke is characterized by a hyperglycemic and pro-inflammatory microenvironment that exacerbates neurovascular dysfunction. However, the blood-brain barrier (BBB) remains a formidable obstacle, restricting the delivery of most therapeutic molecules. To address this, we developed a non-invasive treatment strategy using engineered exosomes. Specifically, we fabricated FGF1-loaded exosomes functionalized with the rabies virus glycoprotein (RVG) peptide (FGF1-RVG Exo). This platform facilitates selective, neuron-targeted delivery of FGF1 to the ischemic penumbra via RVG-mediated transcytosis. In a diabetic stroke mouse model, FGF1-RVG Exo exhibited superior pharmacological efficacy compared to free FGF1, achieving robust therapeutic outcomes with only once-weekly administration. Notably, a single dose during the acute phase elicited a sustained hypoglycemic effect lasting up to two weeks and effectively ameliorated systemic insulin resistance. Locally, the accumulation of exosomes within the lesion led to a significant reduction in infarct volume and cell apoptosis, while promoting neovascularization and the recovery of motor and cognitive functions. This brain-targeted strategy achieves a peripheral-central synergistic modulation, addressing the multi-target requirements of diabetic stroke management. Collectively, our findings provide a novel paradigm for treating diabetic ischemic stroke and a potent strategy for the targeted delivery of growth factors to the central nervous system.

Chronic eosinophilic pneumonia (CEP) is a rare interstitial lung disease. Although CEP has been partially characterized in adults, pediatric data remain scarce, which often leads to diagnostic delays and management uncertainty. This retrospective cohort study analyzed demographic, clinical, laboratory, imaging, bronchoalveolar lavage fluid (BALF), and treatment data from children with CEP between 2014 and 2025. Patients were stratified into ‘Cured’ (complete resolution) and ‘Protracted’ (persistent symptoms or imaging abnormalities > 3 months) groups for exploratory comparison. Thirteen patients (median age 2.92 years; 61.5

Microglia play dual roles in neuroinflammation, driving either detrimental M1 or protective M2 polarization, which critically impacts the outcomes of ischemic stroke. While fibroblast growth factor 20 (FGF20) is established as a neurotrophic factor with neuroprotective properties, its role in regulating microglial polarization remains unclear. This study investigated a novel function of FGF20 in alleviating post-stroke neuroinflammation and its underlying mechanisms. In a rat model of middle cerebral artery occlusion (MCAO), intracerebroventricular administration of FGF20 significantly reduced infarct volume and improved neurological function. RT-PCR analysis revealed that FGF20 bidirectionally regulated cytokine expression, suppressing M1-associated markers (CD86, IL-1β, IL-6, iNOS, TNF-α) while enhancing M2-associated markers (IL-10, Arg-1). Immunofluorescence staining demonstrated that FGF20 attenuated microglia activation in peri-infarct striatum and hippocampus. In vitro, FGF20 counteracted LPS-induced M1 polarization in primary microglia, downregulated the TLR4/NF-κB pathway, and upregulated TREM2 expression. Notably, while the selective FGFR1 inhibitor PD173074 abolished FGF20-induced TREM2 upregulation, it did not reverse the suppression of TLR4/NF-κB, indicating that these two effects are mediated through distinct regulatory mechanisms. These phenotypic shifts were further confirmed by a reduction in CD32/16+ (M1) cells and an increase in Arg1+ (M2) cells. Mechanistically, FGF20 restored the balance between TREM2 and TLR4 signaling, inhibiting NF-κB activation and attenuating neuroinflammatory responses. Collectively, our findings identify FGF20 as a novel dual modulator of microglial polarization that integrates TREM2-mediated immunoregulation with FGFR1-dependent and independent suppression of TLR4/NF-κB pathway. Thus, FGF20 represents a promising therapeutic candidate for ischemic stroke, extending its functional profile from neuroprotection to targeted immunomodulation through phenotype-specific regulation of microglial polarization.

Stroke remains a leading cause of long-term disability, and recovery is often limited by impaired neurorestoration and glial scar–mediated inhibition of axonal regeneration. Although fibroblast growth factor 17 (FGF17) regulates oligodendrocyte plasticity during aging, its therapeutic potential and underlying mechanisms in ischemic stroke remain unclear. We investigated whether FGF17 could promote functional recovery by enhancing neuronal restoration and overcoming glial scar–associated inhibition. Fgf17-positive cell distribution was mapped using Fgf17-reporter mice (Fgf17CreERT2/+;Rosa-CAG-LSL-tdTomato). Focal ischemia was induced in the motor cortex and anterior cingulate cortex of wild-type and Fgf17-deficient (Fgf17−/−) mice via photothrombosis. Recombinant FGF17 was administered intranasally. Functional recovery was evaluated using motor and cognitive behavioral tests. Mechanistic studies were performed using viral tracing, immunofluorescence, and molecular assays focusing on the extracellular signal-regulated kinase (Erk)–serum response factor (SRF) and phospholipase C gamma (PLCγ)–cyclic adenosine monophosphate (cAMP) signaling pathways. FGF17 was predominantly expressed in neurons, whereas its receptor, fibroblast growth factor receptor 3 (FGFR3), was widely distributed. Fgf17−/− mice exhibited larger infarcts and more severe functional deficits, whereas intranasal FGF17 significantly improved motor and cognitive outcomes in both wild-type and knockout mice. Mechanistically, FGF17 promoted oligodendrogenesis and myelin repair by upregulating SRF through the Erk signaling pathway. Concurrently, FGF17 activated the PLCγ–adenylyl cyclase axis, increased intracellular cAMP levels, and enabled axonal regeneration within the inhibitory microenvironment through downregulation of mRNA levels of oligodendrocyte myelin glycoprotein, neurite outgrowth inhibitor A, and myelin-associated glycoprotein. In addition, FGF17 enhanced neuronal survival and preserved dendritic spines via the PI3K–Akt pathway. Overall, FGF17 promotes oligodendrogenesis and enhances the intrinsic regenerative capacity of neurons. These findings identify FGF17 signaling as a promising therapeutic target for neurorestoration after stroke.

Diabetic chronic wounds are marked by a dysregulated immune microenvironment, impaired angiogenesis, and delayed granulation tissue formation, all of which limit the wound recovery under conventional therapies. Effective restoration of the normal healing dynamics, therefore, required not only targeted stimulation of tissue repair but, more critically, reprogramming of the dysregulated immune reaction. To address this, we developed a dual-layer electrospun patch that integrates immune regulation and regenerative promotion through the spatiotemporally controlled release of fibroblast growth factor 21 (FGF21) and basic fibroblast growth factor (bFGF). The poly(lactic acid)/triglycerol monostearate-based patch exhibited MMP-9-responsive and sustained release of FGF21 and bFGF over 14 days. In a type 2 diabetic mouse model, FGF21 induced an M1 to M2 polarization in the cutaneous wounds and regulated the inflammation-related factors to provide a reparative microenvironment, under which bFGF more effectively enhanced angiogenesis and dermal matrix remodeling. Therefore, the bFGF/FGF21 patch significantly accelerated wound closure, re-epithelialization, collagen deposition, and tissue regeneration. This strategy presents a promising approach for treating chronic diabetic wounds.

Acute eosinophilic pneumonia (AEP) is a rare, rapidly progressive respiratory disease characterized by diffuse pulmonary eosinophilia. Its etiology, clinical course, and prognosis in children remain incompletely understood. We conducted a retrospective cohort study at Yuying Children’s Hospital, enrolling children diagnosed with AEP between January 2014 and December 2024. Demographic, clinical, laboratory, radiological, treatment, and outcome data were analyzed. Among 31 patients with pediatric AEP, the highest proportion occurred in autumn (38.7

The robust outer membrane (OM) barrier is a major contributor to antibiotic resistance in multidrug-resistant Gram-negative bacteria (MDR GNB). Disrupting this barrier presents a promising strategy to overcome this challenge. Herein, we propose a carbon monoxide (CO)-driven cascade inhibition strategy to disrupt the OM barrier, aiming to significantly boost the antimicrobial efficacy of existing treatments. As a proof of concept, we developed AIE&CO@G3, a nanogel that combines CO-releasing molecules (CORM-401) and aggregation-induced emission (AIE) photosensitizer (PSs). CO significantly potentiated the antimicrobial activity of AIE PSs-based antimicrobial photodynamic therapy (AIE-aPDT), with similar synergistic effects observed when combined with multiple first-line antibiotics. Mechanistically, CO-induced OM disruption facilitated the penetration of AIE PSs and antibiotics, thereby substantially boosting their efficacy both in vitro (against multiple MDR GNB) and in vivo (in models of MDR P. aeruginosa-infected bacterial keratitis and pneumonia). This was achieved by inhibiting adenosine triphosphate (ATP) synthesis and disrupting the biosynthesis and transport of glycerophospholipids (GPL) and lipopolysaccharides (LPS). This pioneering study highlights CO’s potential in OM disruption and provides a novel strategy for combating MDR GNB infections.

Protein therapeutics offer excellent potential for disease treatments, but are constrained by rapid systemic clearance. Fibroblast growth factor 21 (FGF21), a promising neuroprotective therapeutic candidate, is hindered from further clinical application due to its short half-life. Inspired by the in vivo protein/zinc complexation, we identified a strong interaction between FGF21 and zinc, forming an FGF21/zinc complex through non-covalent interactions. A stable nanocomplex (FGF21/Zinc NC) was further optimized using polyvinylpyrrolidone (PVP) for steric stabilization, which was selected through molecular docking and stability assays. FGF21/Zinc NC demonstrated enhanced pharmacokinetics, with about 3-fold prolonged systemic retention and over 3-fold accumulation in the brain compared to free FGF21. Both in vitro and in vivo, FGF21/Zinc NC outperformed free FGF21, significantly alleviated oxidative stress in neuronal cells, suppressed neuroinflammation to attenuate microglial and astrocyte overactivation, reduced infarct volume by 45%, and accelerated motor recovery in a stroke mouse model. This innovative approach provides a facile and effective strategy to enhance the stability and therapeutic potential of protein-based drugs.

BACKGROUND:Ischemic stroke poses a significant threat to human health. FGF (fibroblast growth factor) 20 is involved in the repair of central nervous system diseases, but it has the shortcomings of short half-life and inability to penetrate the blood-brain barrier. Therefore, to overcome the drawbacks of rhFGF20 (recombinant human FGF20) and explore its role in ischemic stroke, the effects of intracerebral administration of rhFGF20 by heparin-poloxamer hydrogel (HP-rhFGF20 [heparin-poloxamer hydrogel-encapsulated rhFGF20]) in a rat stroke model were the focus of this study. METHODS:A rat model of middle cerebral artery occlusion/reperfusion and oxygen-glucose deprivation-reoxygenation models were established to mimic ischemic stroke in vivo and in vitro, respectively. Endogenous FGF20 levels were measured in patients, ischemic rats, and oxygen-glucose deprivation-reoxygenation-injured neurons. To assess the therapeutic potential, rhFGF20 was administered intracerebrally via heparin-poloxamer hydrogel implants (1 mg/mL, 20 μL) on day 5 poststroke. 2,3,5-Triphenyltetrazolium chloride staining, neurobehavioral tests (including the mNSS test [modified Neuro-Severity Score], the corner test, the rotarod test, the cylinder test, and the Morris water maze test), and Nissl staining were performed to evaluate neurological recovery. Immunofluorescence and Western blotting were conducted to assess the brain repair processes (neurogenesis, neuronal remodeling, and angiogenesis). RESULTS:High expression of FGF20 was detected in the serum of patients with ischemic stroke, the cortex of ischemic rats, and oxygen-glucose deprivation-reoxygenation-injured neurons. Heparin-poloxamer increased the stability and bioavailability of rhFGF20. HP-rhFGF20 attenuated neurobehavioral deficits and infarct volume in ischemic stroke rats. HP-rhFGF20 inhibited neuronal cell death, microglial activation, and glial scar formation on day 7 post-implantation. Moreover, HP-rhFGF20 promoted the proliferation, migration, and differentiation of neural stem cells and improved neuronal plasticity and angiogenesis in ischemic stroke rats. CONCLUSIONS:HP-rhFGF20 promoted functional recovery in ischemic stroke rats by enhancing neurogenesis and angiogenesis. The combination of growth factors and biomaterials provides a promising therapeutic strategy for central nervous system diseases. REGISTRATION:URL: http://www.chictr.org.cn; Unique identifier: ChiCTR2100051104.

Ischemic stroke is a frequent cause of mortality and disability, and astrocyte reactivity is closely associated with injury outcomes. Fibroblast growth factor 21 (FGF21), an endogenous regulator, has been shown to perform pleiotropic functions in central nervous system (CNS) disorders. However, studies on neurological diseases have paid little attention to the effects and detailed mechanisms of FGF21 in astrocytes. Here, we found elevated serum levels of FGF21 in stroke patients and transient middle cerebral artery occlusion (tMCAO) mice. In the peri-infarct cortex, microglia and astrocytes serve as sources of FGF21 in addition to neurons. MRI and neurobehavioral assessments of wild-type (WT) and FGF21−/− tMCAO model mice revealed a deteriorated consequence of the loss of FGF21, with exacerbated brain infarction and neurological deficits. Additionally, combined with the pharmacological treatment of WT mice with recombinant human FGF21 (rhFGF21) after tMCAO, FGF21 was identified to suppress astrocytic activation and astrocyte-mediated inflammatory responses after brain ischemia and participated in controlling the infiltration of peripheral inflammatory cells (including macrophages, neutrophils, monocytes, and T cells) by modulating chemokines expression (such as Ccl3, Cxcl1, and Cxcl2) in astrocytes. Furthermore, rhFGF21 was shown to boost the production of neurotrophic factors (BDNF and NGF) in astrocytes, and by which rescued neuronal survival and promoted synaptic protein expression (postsynaptic density protein-95 (PSD-95), synaptotagmin 1 (SYT1), and synaptophysin) in neurons after ischemic injury. Overall, our findings implicate that FGF21 acts as a suppressor of astrocyte activation, and exerts anti-inflammatory and neurotrophic effects after ischemic brain injury through its action on astrocytes, offering an alternative therapeutic target.

Background: Ultraviolet B (UVB) irradiation can damage skin tissue. Diabetes aggravates skin lesions. Fibroblast growth factor 21 (FGF21) is significantly involved in exerting protective effects and facilitating tissue repair. Therefore, this study aimed to investigate the impact of recombinant human FGF21 (rhFGF21) on diabetic skin affected by UVB damage.Methods: UVB irradiation (270 mJ/cm2) was administered to diabetic mice for 5 consecutive days to establish UVB-irradiated skin injury, and rhFGF21 was administered daily after irradiation. Human immortalized keratinocytes (HaCaT) and mouse peritoneal macrophages (MPMs) were cultured under high glucose (HG) conditions for 3 days, followed by treatment with rhFGF21 for 1 h before UVB irradiation or lipopolysaccharide (LPS) stimulation. We analyzed the effects of UVB irradiation on diabetic skin via laser Doppler flowmetry, histopathological staining, TUNEL assays, RT-PCR, Western blotting, MTT assays and Hoechst 33258 staining.Results: Our findings indicated that the skin of diabetic mice was more severely damaged by UVB irradiation, and rhFGF21 alleviated this damage. RhFGF21 inhibited apoptosis and inflammatory responses in the skin tissues of diabetic mice. These changes were primarily reflected in increase of the sirtuin 1 (SIRT1) level in epidermal cells and peritoneal macrophages of mice. Moreover, rhFGF21 not only increased the survival rate of HaCaT cells but also decreased the generation of pro-inflammatory cytokines in MPMs. Notably, SIRT1 inhibitor (EX527) was capable of reversing these effects.Conclusions: RhFGF21 attenuates UVB-induced damage to the skin of diabetic mice, predominantly by suppressing epidermal cell apoptosis and macrophage-mediated inflammatory responses via the SIRT signaling pathway.

Stroke is the second leading cause of death and the primary cause of disability worldwide, yet effective treatments to restore neurological function remain limited. Fibroblast growth factor 20 (FGF20), a promising neurotrophic factor with demonstrated efficacy in neurological disorders, faces a critical translational barrier due to its poor blood-brain barrier (BBB) permeability. To address this limitation, we developed genetically engineered rabies virus glycoprotein (RVG)-modified extracellular vesicles loaded with FGF20 (RVG-FGF20-EVs) for targeted ischemic brain delivery. Systemic administration of RVG-FGF20-EVs in a mouse middle cerebral artery occlusion (MCAO) model significantly reduced infarct volume, enhanced neuroplasticity, and improved long-term functional recovery. Mechanistic investigations revealed that RVG-FGF20-EVs exhibit a distinct miRNA cargo profile, characterized by significant upregulation of miR-181b-5p. Dual-luciferase reporter assays confirmed phosphatase and tensin homolog (PTEN) as a direct target of miR-181b-5p. Our findings demonstrate that RVG-FGF20-EVs promote neuroplasticity and functional recovery post-stroke, mediated at least partially through the miR-181b-5p/PTEN pathway. This study represents the first application of engineered RVG-EVs for efficient FGF20 brain delivery for efficient FGF20 delivery, establishing their unique efficacy in treating ischemic stroke and providing a multifunctional platform for treating neurological disorders. Further optimization and standardization are needed to translate this promising platform into clinical applications. In conclusion, RVG-FGF20-EVs constitute a promising novel therapeutic strategy for ischemic stroke.

Bacterial biofilms and their microenvironment are significant challenges that must be faced in the design of antibacterial drugs. Microenvironment-responsive mimetic peroxidases (POD) have been demonstrated to be an efficient solution to eliminating bacterial biofilms. However, they inevitably require additional H2O2 and/or acid due to the poor permeabilities towards biofilms. Herein, we report POD-like copper-doped carbon dots (named CuCD1) synthesized through a facile microwave-assisted carbonization manner. The characteristics of ultrasmall size (< 5 nm) and positive charge enabled it to possess good penetrability toward bacterial biofilm. As expected, CuCD1 showed great damage to bacteria due to the generation of hydroxyl radicals (center dot OH), which originated from the catalytic decomposition of endogenous H2O2 under a weak acid bacterial biofilm microenvironment. This highly increased oxidative stress resulted in the alteration of cell membrane permeability, subsequent cell death, and the final eradication of bacterial biofilm and the exposed bacteria. Moreover, to verify the practicality in vivo, CuCD1 was introduced to a routine hydrogel that was crosslinked by carboxymethyl chitosan (CMCS) and oxidized dextran (ODEX). In comparison with the control groups, the composite hydrogel, i.e., CuCD1-CMCS-ODEX revealed better antibacterial performance and thus accelerated wound healing and collagen disposition. This work would open opportunities to design CDs-based biofilm microenvironment-responsive antibacterial nanoagents.

Microglial phagocytosis is a highly energy-consuming process that plays critical roles in clearing neurotoxic amyloid-beta (A beta) in Alzheimer's disease (AD). However, microglial metabolism is defective overall in AD, thereby undermining microglial phagocytic functions. Herein, we repurpose the existing antineoplastic drug lonidamine (LND) conjugated with hollow mesoporous Prussian blue (HMPB) as a "microglial energy modulator" (termed LND@HMPB-T7) for safe and synergistic A beta clearance. The modified blood-brain barrier penetrating heptapeptide (T7) enables efficient transport of LND@HMPB-T7 to the AD brain. LND in LND@HMPB-T7 could fuel A beta phagocytosis by stimulating microglial adenosine triphosphate (ATP) production, whereas HMPB with catalase and superoxide dismutase-mimicking activities substantially alleviates the mitochondrial side effects commonly associated with LND and thus further enhances ATP production. The synergism of LND and nanozyme affords a high microglial A beta clearance efficacy without triggering mitochondrial dysfunction. In vivo experiments ascertain that LND@HMPB-T7 could synergistically promote phagocytic clearance of A beta, relieve neuroinflammation and ameliorate cognitive function in AD mice. These findings indicate that LND@HMPB-T7 holds tremendous clinical potential as a repurposed drug for AD treatment.

Containment of secondary injury following severe traumatic brain injury (sTBI) is crucial for preserving neural tissue and function, especially when a dysregulated neuroimmune response exacerbates inflammation. However, effective therapeutic interventions targeting neuroimmune remodeling remain lacking. In this study, fibroblast growth factor 21 (FGF21) is identified as a promising immunomodulatory candidate, and a dual-layer electrospun scaffold is developed for efficient FGF21 delivery to the brain. FGF21 is stabilized within poly(lactic acid) (PLA), as confirmed by molecular docking, and incorporated into a PLA/triglycerol monostearate (PT) nanofiber inner layer for matrix metalloproteinase-9 (MMP-9)-responsive drug release. A crosslinked zein/gelatin (CZG) outer layer is added to support dura mater recovery. In a murine sTBI model, RNA sequencing revealed that FGF21 modulates neuroinflammation by suppressing type I interferon signaling and downstream chemotaxis, thereby shifting microglia from an aggressive pro-inflammatory to a restorative phenotype, with concurrent reductions in microglial proportion and amoeboid morphology. Magnetic Resonance Imaging (MRI)Magnetic Resonance Imaging imaging and behavioral assessments further confirmed the neuroprotective effects of FGF21@PT/CZG and demonstrated improvements in sensorimotor and neurological functions. These findings suggest that this nanofibrous scaffold offers a promising therapeutic strategy for targeted immunomodulation and functional recovery following sTBI.

BACKGROUND:Disease-modifying treatments with anti-epileptic effects are currently unavailable and urgently required for temporal lobe epilepsy (TLE). Combined therapy targeting multiple mechanisms may offer a promising anti-epileptic strategy, given the complex processes underlying epileptogenesis. PURPOSE:This study evaluates the effects of Edaravone Dexbroneol, a combination of Edaravone and Dexborneol in 4:1, on rat and mouse TLE models and an in vitro epileptiform activity model. METHODS:The Pilocarpine-induced rat TLE model and the Kainic acid-induced mouse TLE model were used to assess the in vivo effect of Edaravone and/or Dexbornel. Primary neurons were utilized to evaluate the in vitro effect of drugs using calcium imaging, electrophysiological and biochemical analyses, as well as RNA sequencing. RESULTS:Treatment of Edaravone Dexbornel during the latent period significantly alleviated epileptic seizures in rodents, mitigated cognitive impairment, and inhibited neuronal loss and astrocytic activation. In vitro, Edaravone Dexborneol inhibited the action potentials and protected primary hippocampal neurons from Mg2+-free-induced neurite injury. All these effects were significantly more pronounced in the group treated with the Edaravone Dexborneol mixture compared to either drug used individually. Furthermore, Edaravone can significantly inhibit Mg2+-free-induced calcium oscillations in primary neurons, probably by promoting the deactivation of NMDA receptors. RNA sequencing and RT-PCR analysis revealed that synergetic regulation of lipid metabolism, oxidative stress, apoptosis, and calcium signaling probably underlay the neuroprotective effect of Edaravone Dexbornel on epileptic neurons. CONCLUSION:Edaravone Dexborneol exhibits antiepileptic effects and may fill the gap in disease-modifying treatments for TLE.

The heart, an organ with a continuously high demand for energy, inherently lacks substantial reserves. The precise mechanisms that prioritize energy allocation to cardiac mitochondria, ensuring steady-state ATP production amidst high-energy organs, remain poorly understood. Our study sheds light on this process by identifying a two-strata flux system driven by the starvation hormone FGF21. We demonstrate that systemic disruptions in interorgan metabolite mobilization and transcardiac flux, arising from either adipose lipolysis or hepatic ketogenesis due to FGF21 deficiency, directly impair cardiac energetic performance. Locally, this impairment is linked to compromised intracardiac utilization of various metabolites via ketolysis and oxidation pathways, along with hindered mitochondrial biogenesis, TCA cycle, ETC flow, and OXPHOS. Consequently, the heart shifts to a hypometabolic, glycolytic, and hypoenergy state, with a reduced capacity to cope with physiological stressors such as fasting, starvation, strenuous exercise, endurance training, and cold exposure, leading to a diminished heart rate, contractility, and hemodynamic stability. Pharmacological or genetic restoration of FGF21 ameliorates these defects, reenergizing stress-exhausted hearts. This hierarchical energy-prioritizing mechanism is orchestrated by the LKB1-AMPK-mTOR energy stress response pathways. Disrupting cardiac LKB1 or mTOR pathways, akin to stalling mitochondrial energy conduits, obstructs the FGF21-governed cardiac energetic potential. Our findings reveal an essential two-strata energy flux system critical for cardiac energetic efficiency regulated by FGF21, which spatiotemporally optimizes interorgan and transcardiac metabolite flux and intracardiac mitochondrial energy sufficiency. This discovery informs the design of strategies for treating cardiac diseases linked to mitochondrial or energy deficiencies.