Under normal fatty acid oxidation conditions, 70% of Adenosine triphosphate (ATP) in the myocardium is derived from fatty acid oxidation; the other part is derived from glucose oxidation (24). In the septic state, interleukin-1β (IL-1β) and other inflammatory factors can down-regulate low-density lipoprotein receptor (LDLR) expression in cardiomyocytes. At the same time, reducing LDLR and fatty acid transporter CD36 can inhibit lipid uptake in cardiomyocytes (24, 25). Sepsis inhibits intracellular fatty acid oxidation, ultimately reducing ATP production in cardiomyocytes and leading to myocardial dysfunction.

Mitochondrial oxidative stress occurs in the early stages of sepsis. When the body is infected, inflammatory cells (such as neutrophils and macrophages) can release some inflammatory mediators, such as cytokines and chemokines, which can further activate oxidative stress reactions and increase oxidative stress. At the same time, the hypoxic state and metabolic abnormalities during the infection process can also lead to increased mitochondrial free radical production. Oxidative stress can impair the mitochondrial oxidative phosphorylation system and respiratory chain, leading to mitochondrial dysfunction and disturbances in myocardial energy metabolism and calcium ion homeostasis imbalance. Oxidative stress can also cause the mitochondrial permeability transition, which releases proteins such as cytochrome C and apoptosis-inducing factors from the mitochondria, further inducing apoptosis of myocardial cells. In addition, oxidative stress can oxidatively damage mitochondrial DNA, down-regulating mitochondrial gene expression and synthesis of mitochondrial proteins, ultimately leading to functional and structural abnormalities of myocardial cells. Several studies have confirmed the oxidative-reductive imbalance in sepsis patients (26–30).

Tissue hypoxia inhibits the mitochondrial electron transport chain and oxidative phosphorylation, reduces ATP synthesis, and increases inducible nitric oxide synthase (NOS) expression to produce a significant amount of nitric oxide (NO) (31). It has been reported that a considerable amount of NO can inhibit respiratory chain complexes, producing substantial ROS. Combining NO and superoxide can induce protein dysfunction, lipid peroxidation, and DNA damage. At the same time, NO competes for the oxygen binding site of cytochrome C oxidase, leading to dysfunction of the myocardial mitochondria electron transport chain, resulting in mitochondrial damage and myocardial cell energy failure (32). In addition, by reducing the response of myofibrils to calcium, NO can relax the vascular smooth muscle to alter the pre- and post-cardiac load and downregulate myocardial perfusion β receptor expression, altering adrenal hormone levels and affecting the redox function of mitochondria. Reactive oxygen species can also alter mitochondrial ultrastructure, damage mitochondrial biosynthesis, and affect mitochondrial function through oxidative modification of mitochondrial DNA and other macromolecules, promoting cell apoptosis and aggravating SIMD (33). Inhibition of cytochrome C oxidase disrupts the activity of the mitochondrial electron transport chain enzyme complex (34), so the cell cannot produce ATP through oxygenation, which eventually results in the production of substantial ROS and inhibits the oxidative phosphorylation process (35).

When mitochondrial dysfunction persists, damaged cardiomyocytes produce ROS, and ROS-mediated oxidative stress causes mitochondrial dysfunction, ultimately leading to SIMD (36). When oxidative/antioxidant imbalance occurs, excessive ROS can also directly damage the membrane structure and organelles of cardiomyocytes, thereby increasing the cell membrane permeability, leading to cardiomyocyte dysfunction and even cell autolysis (37). Studies have reported that ROS/reactive nitrogen species (RNS) can cause lipid peroxidation, protein nitrification, and protein oxidation in endothelial cells, leading to abnormal adhesion of leukocytes and platelets and increasing capillary permeability. Endothelial NO synthase (eNOS) is upregulated in endothelial cells, which weakens endothelial cell-dependent vasodilation and aggravates microcirculatory disorders (38). Oxygen free radicals directly attack mitochondrial membrane proteins and nucleotides, disrupting the integrity of the mitochondrial membrane and the activity of biological enzymes, resulting in cell damage and death. Damage to the mitochondrial membrane can lead to oxidative phosphorylation disorders in the respiratory chain, impairing ATP generation and leading to disorders in energy metabolism (39). Functional proteins on the surface of mitochondria are involved in signal transduction, Ca²⁺ regulation and other processes to cause abnormal signal transduction and excitation-contraction coupling disorders in cardiomyocytes (40).

The production and release of a considerable amount of ROS and RNS lead to structural changes of structural proteins at the mitochondrial permeability transition pore (mPTP). The pathological opening of mPTP increases mitochondrial permeability and causes mitochondrial damage (41). Activation of downstream signaling pathways can lead to cardiomyocyte apoptosis and necrosis (42, 43). Opening of mPTP downregulates expression of the mitochondrial complex Ⅱ/V and significantly decreases ATP concentration in cardiomyocytes (44, 45), leading to mitochondrial dysfunction (46, 47). High expression of the pro-apoptotic protein Bax can cause mPTP to open. In contrast, the anti-apoptotic protein Bcl-2 can inhibit the process. Regulation of Bax/Bcl-2 at mPTP opening alters mitochondrial membrane permeability, ultimately leading to cardiomyocyte apoptosis (48).

When SIMD occurs, the myocardial autophagy mechanism gets activated to reduce its damage. Autophagy has a cytoprotective effect and can adapt to the pathological state of the myocardium (49). This dynamic process allows damaged cellular components, such as organelles and misfolded proteins, to be phagocytosed, packaged, and fused to lysosomes for degradation. Tumor necrosis factor-α (TNF-α) can induce cardiomyocyte death by upregulating Drp1 expression and enhancing mitochondrial translocation, inhibiting the autophagy function of cardiomyocytes, and leading to irreversible damage that accelerates the development of SIMD (50). Inflammatory mediators and oxidative stress can activate the caspase-3 pathway and lead to apoptosis of cardiomyocyte (51, 52). Endotoxin can activate caspase-3, caspase-8, and caspase-9 of cardiomyocytes, which not only induces end-stage nuclear apoptosis, myofilament, and sarcomere disruption in the myocardium but also decreases the contractile response of ventricular myocytes to norepinephrine (53). While caspase-3 inhibitor application can improve endotoxin-induced myocardial systolic dysfunction (54), LPS can inhibit expression of miR-499, and increase expression of sex-determining region Y (SRY), SRY type HMG box (SOX6) and programmed cell death 4 (PDCD4). In addition, studies have reported that LPS activates the Bcl-2 family signaling pathway, resulting in increased expression of pro-apoptotic genes and decreased expression of anti-apoptotic genes. These results suggest that the miR-499-SOX6/PDCD4-Bcl2 signaling pathway is involved in the pathophysiology of SIMD (55).

Pyroptosis is distinct from apoptosis and cell necrosis. Both apoptosis and pyroptosis involve DNA breakage and destruction of the cell membrane, resulting in leakage of cell contents and complete cell death. The difference between the two is that the execution of apoptosis depends on the mixed lineage kinase domain-like protein (MLKL), which selectively leads to cell membrane oligomerization and plasma membrane translocation, resulting in a change in intracellular and extracellular osmotic pressure and cell rupture. However, pyroptosis depends on the Gasdermin D protein, which does not selectively destroy the cell membrane, but instead leads to the release of cell contents, cell flattening, and cell death (56, 57). The NLR Family Pyrin Domain-Containing 3 (NLRP3) inflammasome/caspase-1/IL-1β pathway may be involved to some extent in the occurrence of systemic inflammatory response syndrome (SIRS) (58). Treatment with an NLRP3 inhibitor in septic mice can significantly inhibit NLRP3-mediated inflammasome formation, caspase-1 activation, and IL-1β secretion and has been shown to be protective for the myocardium (59).

Cardiac dysfunction caused by a calcium imbalance in sepsis is related to the reduction in L-type calcium channels, inhibition of the sarcoplasmic reticulum calcium pump, abnormal ryanodine receptors, and decreased myofilaments sensitivity to calcium (60). In sepsis, microcirculation disorders associated with myocardial ischemia and hypoxia, on the one hand, directly affect the production of ATP, reduce the activity of the sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase 2 (SERCA2), accompanied by the decrease in phospholamban (PLB) phosphorylation, and lead to impaired function of the sarcoplasmic reticulum in the uptake of free calcium. On the other hand, dysfunction of the membrane pump, accumulation of intracellular acid metabolites, and increased Na⁺/H⁺ exchange can lead to the opening of voltage-dependent calcium channels in the cell membrane. A large amount of extracellular Ca²⁺ flows inwards. Exceeding the regulatory capacity of the sarcoplasmic reticulum and calcium-binding protein results in intracellular calcium overload (61). When calcium overload occurs, a substantial amount of Ca²⁺ floods into cells and accumulates in mitochondria, resulting in dysfunction of the mitochondrial respiratory, an increase in oxygen free radicals, and lipid peroxidation damage in mitochondria and cardiomyocytes. At the same time, calpain, calcium-dependent phospholipase, calcium-dependent nucleotide endonuclease, and other digestive enzymes are activated, which can also lead to the apoptosis of cardiomyocytes (62).

It has been experimentally demonstrated that PLB mediates the transport of Ca²⁺ between the cytosol and the sarcoplasmic reticulum. Dephosphorylation of PLB can increase calcium pump activity and Ca²+ flux, promoting myocardial contraction. Phosphorylation of PLB can inhibit calcium pump activity and reduce the flow of Ca²⁺, thereby promoting myocardial relaxation (63). Excessive leakage of Ca²⁺ from the sarcoplasmic reticulum and influx across the cell membrane can activate calmodulin-dependent proteins and lead to cardiomyocyte death (60).

Decreased sensitivity of cardiac myofilaments to Ca²⁺ prolongs myocardial contraction and ventricular density, thereby impairing the Frank-Starling effect of cardiomyocytes. The reduced calcium sensitivity may be due to the downregulation of protein kinase C (PKC) and Rho kinase expression by inflammatory factors, such as IL-1β (64). In turn, the increase in Ca²⁺ in immune cells of sepsis patients can promote the production of cytokines by LPS-induced monocytes/macrophages, exacerbate inflammatory responses and vascular leakage, and ultimately lead to impaired cardiac function (65).

During the SIMD process, endotoxin can inhibit the cardiac autonomic nerve conduction pathway, induce apoptosis of neuronal and glial cells, and trigger the depolarization current of the sinoatrial node controlled by the cholinergic nerve due to the increase of plasma cytokines, resulting in the loss of heart rate variability (89–91). High concentrations of catecholamines can also decrease heart rate variability and response to endogenous catecholamines. Loss of heart rate variability indicates a high probability of progression to multi-organ failure and a poor prognosis in sepsis (92).

When sepsis occurs, factors such as inflammatory mediators and abnormal distribution of intracellular and extracellular Ca²⁺ lead to endothelial dysfunction of the microcirculation vessels and increased capillary permeability, decreasing the volume of microcirculation vessels (93). Overproduction of NO, decreased reactivity of angiotensin Ⅱ, catecholamines, and other vasoconstrictor factors, and inhibition of signal transduction pathways mediate decreased vascular tone, resulting in systemic hypotension and microvascular response (94). Thrombin deposition leads to microthrombi, inflammatory cell migration, and leukocyte adhesion, which increase blood viscosity and lead to microcirculation disorders. The decrease in microcirculation vessel volume, vascular tone, and microcirculation disorder in sepsis leads to reduced myocardial perfusion, affecting the uptake and utilization of oxygen by cardiomyocytes, the systolic and diastolic functions of the heart to varying degrees and ultimately leading to SIMD. At the same time, the myocardial structure is damaged after sepsis, manifested as calcium overload, increased expression of calpain-1, and enzymatic degradation of actin and myosin, inducing myocardial injury and apoptosis and leading to SIMD (95).

Numerous studies have demonstrated that miRNAs regulate the inflammatory response in SIMD mainly through signaling pathways, including TLR4, MAPK, NF-κB, PI3 K/AKT, JNK, STAT3, and transforming growth factor-β1 (TGF-β1)/Smads and the expression of inflammatory factors such as HMGB1, TNF-α, IL-6, and IL-1β (Table 1). For instance, miR-93-3p can inhibit the TLR4 signaling pathway, protecting against LPS-induced cardiomyocyte inflammation and apoptosis (96). By targeting forkhead box transcription factor 3a (FOXO3A), miR-29b-3p can inhibit the activation of MAPKs and nuclear translocation of NF-κB to block LPS-activated NF-κB signaling, thereby reducing inflammatory injury (97). On the other hand, the overexpression of miR-101-3p/miR-135a can activate the MAPK/NF-κB pathway, inducing SIMD (98, 99). Furthermore, low expression of miRNAs such as miR-23a-3p (107), miR-23b (106), miR-330-5p (100), and others plays a role in the activation of the NF-κB signaling pathway, thereby inducing SIMD. By targeting the Bromodomain-containing protein 4 (BRD4), miR-375-3p can activate the PI3 K/AKT pathway and alleviate SIMD in rats (108). Additionally, miR-155 can target JNK-related inflammatory signals and β-arrestin 2 (ARRB2)-mediated immunosuppression to attenuate cardiac insufficiency and improve survival in late-stage sepsis patients (109). MiR-193-3p (12) and miR-223 (110) can inhibit inflammation and relieve SIMD-related symptoms by targeting the STAT3 signaling pathway. Lastly, miR-195 can activate the TGF-β1/Smads pathway to promote cardiac remodeling and regulate the inflammatory response in septic rats (111).

These miRNAs, through their involvement in inflammation, not only contribute to the development of myocardial injury in sepsis but also play a crucial role in sepsis-induced lung injury, renal injury, intestinal damage, and brain injury. Research has shown that miR-144-3p and miR-146a-5p activate the Janus kinase (JAK)/transcription (STAT) signaling pathway (139) and promote dendritic cell activation and glycolysis (140) by targeting Caveolin-2 and autophagy-related 7 (ATG7), respectively, accelerating the occurrence of Sepsis-associated acute lung injury (SA-ALI). miR-21 (141, 142) and miR-223 (143) worsen SA-ALI by targeting the TLR4/NF-κB pathway, miR-23a-3p targets the Polo-like kinase 1 (PLK1)/STAT1/STAT3 signaling pathway to promote M1 polarization of macrophages (144), and miR-23b mainly targets zonula occludens-1 (ZO-1) to induce vascular leakage and aggravate SA-ALI (145). MiR-21-3p promotes the progression of Sepsis-associated acute kidney injury (SA-AKI) by regulating the AKT/cyclin-dependent kinase 2 (CDK2)/forkhead box-1 (FOXO1) pathway [Lin, et al., (146)]. MiR-214-5p exacerbates SA-AKI by inhibiting the glucagon-like peptide-1 receptor (GLP-1R)/AMPK axis [Guo, et al., (147)]. MiR-214 targets KLF6 [Zhao, et al., (148)] or PTEN [Sang, et al., (149)] to regulate the AKT/mTOR pathway and participate in the pathological process of septic renal injury. Overexpression of MiR-133a-3p promotes apoptosis of septic intestinal epithelial cells by downregulating transgelin-2 (TAGLN2) (150). MiR-141 induces septic intestinal injury through the TLR4 pathway (151). Upregulation of miR-146b-5p inhibits cell proliferation and migration by targeting Cyclin D2 (Ccnd2) and plays a crucial role in the development of septic intestinal injury (152). MiR-25-5p alleviates LPS-induced inflammation, reactive oxygen species generation, and brain injury by negatively regulating the expression of TXNIP (153). Additionally, miR-146a-5p targets TLR7 to regulate innate immune responses in microglia/astrocytes and the intact brain (154).

Mitochondria are the only organelles responsible for generating ATP in body cells. Therefore, their normal function is very important for maintaining the normal pathophysiological functioning of cells, tissues and organs. Because of its continuous pumping action, the heart requires a large amount of ATP to maintain its normal contractile activity. Therefore, the mitochondria in cardiomyocytes must produce adequate energy in the form of ATP through oxidative phosphorylation. In addition, mitochondria play an important role in maintaining proper cardiac function by regulating calcium homeostasis, ROS and related signal transduction in cardiomyocytes.

As shown in Table 2, miR-484 promotes mitochondrial fission by targeting Yes Associated Protein 1, thereby aggravating LPS-induced cardiomyocyte apoptosis and inflammation (155). MiR-324-5p can target proteasome 26S subunit non-ATPase 4 (PSMD4) and act on mitochondrial fission regulator 1 (Mtfr1) to change mitochondrial morphology and promote cardiomyocyte death (156). CircTLK1 can sponge miR-17-5p, activate the poly(ADP-ribose) polymerase 1 (PARP1)/HMGB1 axis, and aggravate the oxidative damage of mitochondrial genome (mtDNA), resulting in mitochondrial dysfunction and cardiomyocyte apoptosis in sepsis (157). Both miR-21-3p and miR-93-5p target SH3 domain-containing protein 2 (SORBS2), potentially causing mitochondrial ultrastructural damage and autophagy, leading to cardiac dysfunction in SIMD (158, 159). MiR-210-3p targets NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4 (NDUFA4) causing mitochondrial dysfunction and promoting the pathogenesis of SIMD (160). LPS can upregulate MiR-29a, further damaging mitochondrial function, reducing mitochondrial membrane potential (MMP), generating ROS, and damaging cardiomyocytes (162). In sepsis, serum exosomes from patients with SIMD can target the transcription of glucose transporter GLUT1 (SLC2A1) in cardiomyocytes through miR-1262, inhibiting mitochondrial glycolysis rate and promoting cardiomyocyte apoptosis, ultimately aggravating myocardial injury (163). LPS upregulates miR-208a-5p in sepsis, which has been shown to activate the NF-κB/HIF-1α axis mediated by SOCS2, causing mitochondrial swelling and ultimately leading to cardiomyocyte apoptosis (164). MiR-194-5p targets DUSP9 and is involved in oxidative stress and mitochondrial dysfunction, exacerbating sepsis-induced cardiomyopathy (165). In addition, studies have shown that the lncRNA RMRP can regulate post-transcriptional function, inhibit mitochondrial damage, and attenuate cardiomyocyte apoptosis in SIMD by inhibiting miR-1-5p from targeting HSPA4 (161). lncRNA MCM3AP-AS1 alleviates sepsis-induced cardiomyopathy by improving inflammation, oxidative stress, and mitochondrial function through the inhibition of the miR-501-3p/CADM1/STAT3 axis (166).

Additionally, studies have shown that these miRNAs can regulate mitochondrial function and contribute to the progression of liver injury in sepsis. Upregulation of miR-155 exacerbates sepsis-induced liver damage by targeting nuclear factor E2-related factor (Nrf-2) and mediating oxidative stress-induced endoplasmic reticulum stress and mitochondrial dysfunction (167). In contrast, the inhibition of miR-155 attenuates sepsis-induced liver injury by enhancing the expression of suppressor of cytokine signaling 1 (SOCS1) and blocking the JAK/STAT pathway (168).

Oxidative stress refers to the imbalance between oxidation and antioxidation in the intracellular and extracellular environments. As a result, harmful molecules such as oxygen free radicals accumulate, causing oxidative damage. In sepsis patients, the level of oxidative stress is significantly increased due to various factors such as infection and inflammatory reactions. The effect of oxidative stress on cardiac function is multifaceted. First, oxidative stress can cause myocardial cell damage and apoptosis, ultimately leading to a decrease in normal myocardial contractile function and heart failure. Second, oxidative stress can lead to dysfunction of endothelial cells and smooth muscle cells in the cardiovascular system, leading to impaired vascular contraction function and microcirculation disorder, reducing blood supply and oxygen delivery to the heart. Third, oxidative stress can activate inflammation and blood coagulation, exacerbating cardiac load and hypoxia, leading to serious consequences such as myocardial ischemia and myocardial infarction. Therefore, oxidative stress plays an important role in sepsis-induced cardiac dysfunction, and maintaining oxidant/antioxidant balance with antioxidant therapy may be an important strategy for preventing and treating SIMD (Table 3).

LPS-treated H9C2 cells inhibited the expression of miR-124-3p, upregulated specific protein 1 (SP1), and targeted histone deacetylase 4 (HDAC4)/Hypoxia-inducible factor-1α (HIF-1α) to mediate oxidative stress, causing myocardial injury in septic rats (169). LPS can inhibit the expression of miR-125b, resulting in the upregulation of downstream target gene transcription 3 (STAT3) mRNA, which binds to the promoter of HMGB1, ultimately leading to the generation of ROS, which can cause autophagy and damage to the cardiomyocytes (170). In sepsis, miR-122-5p level is increased, which reduces the activities of antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-px), leading to the generation of ROS and oxidative stress in cardiomyocytes. At the same time, the upregulation of TNF-α, IL-6 and IL-1β coupled with the cleavage of caspase-3 leads to cardiomyocyte apoptosis (173). Overexpression of miR-340-5p can reduce oxidative stress-induced injury in cardiomyocytes and improve cardiac dysfunction in sepsis by targeting MyD88 (171). Up-regulation of miR-335 can protect cardiomyocytes against oxidative stress and alleviate myocardial cell injury in sepsis (172). lncRNA SNHG1 shows a protective effect on cardomyocyes in sepsis by targeting miR-181a-5p/X-linked inhibitor of apoptosis (XIAP) axis. This activity inhibits oxidative stress, inflammation, and apoptosis, which enhances cardiomyocyte viability, and finally alleviates myocardial cell injury (174).

MiRNAs play a role in SIMD pathogenesis through affecting cardiomyocyte viability and regulating various pathways critical to cardiomyocyte survival, differentiation, and proliferation, and promoting cardiomyocyte apoptosis, pyroptosis, and necroptosis (Table 4). Studies have shown that in the rat model of SIMD, miR-21 (175), miR-106b-5p (176), miR-642a (177), and others may affect the viability of cardiomyocytes, suggesting their role in the pathological process of SIMD. MiR-141 loaded into exosomes derived from bone marrow mesenchymal stem cells can inhibit the expression of phosphatase and tensin homolog (PTEN), further enhance the activity of β-catenin, improve myocardial injury, and reduce inflammatory cell infiltration and apoptosis in septic mice (212). Overexpression of miR-539-5p can promote the survival and proliferation of LPS-treated H9c2 cells and inhibit apoptosis by targeting interleukin-1 receptor-associated kinase-3 (IRAK3) (179). MiR-221-3p, miR-221-5p, miR-155-5p, and miR-222-5p can promote the survival of cardiomyocytes by down-regulating three apoptosis-related proteins: brassinosteroid insensitive 1-associated kinase 1 (BAK1), P53, and PTEN (181). Inhibition of miR-214-3p has been implicated involved in the pathogenesis of SIMD, whereas its overexpression can attenuate SIMD by inhibiting the expression of PTEN, inducing myocardial autophagy, and activating AKT/mTOR pathway (187). Downregulation of miR-16 (188), miR-150-5p (191, 192), miR-501-5p (193), and others promotes myocardial injury in sepsis by regulating apoptosis-related proteins such as Bax/Bcl-2 apoptosis family proteins and caspase-3. Upregulation of miR-21 (190), miR-24 (189), miR-7a-5p (196), and others has also been confirmed to promote apoptosis in septic cardiomyocytes. One study found that exosomes derived from sepsis patients’ blood can upregulate miR-885-5p in AC16 cells, downregulate homeobox containing 1 (HMBOX1) and increase IL-1β and IL-18, further promoting pyroptosis of AC16 cells (184). Similarly, the upregulation of miR-138-5p (185) and downregulation of miR-590-3p (186) can cause cardiomyocyte pyroptosis, leading to SIMD. MiR-96-5p targets NLRP3, leading to cardiomyocyte pyroptosis and exacerbating septic cardiomyopathy (211). Additionally, USF2 transcriptionally inhibits miR-206, activating the RhoB/ROCK pathway, which further promotes pyroptosis in septic cardiomyocytes (210).

Ferroptosis, on the other hand, is a form of regulated cell death that is distinct from apoptosis, necrosis, and autophagy. It is characterized by the accumulation of lethal levels of lipid peroxides, particularly in the presence of iron, leading to cellular membrane damage and rupture. Ferroptosis is primarily driven by iron-dependent oxidative stress, where excessive reactive oxygen species (ROS) oxidize polyunsaturated fatty acids in cell membranes, resulting in lipid peroxidation. This process is tightly regulated by key enzymes, such as glutathione peroxidase 4 (GPX4), which normally protects cells from lipid peroxidation. When this defense mechanism is overwhelmed or inhibited, ferroptosis occurs. Unlike other forms of cell death, ferroptosis does not involve the classic apoptotic markers, but rather is marked by specific molecular pathways linked to iron metabolism and lipid peroxidation.

Ferroptosis has been reported in cardiac tissues of patients with sepsis, suggesting its potential role in myocardial injury in SIMD. Recent studies have shown that ferroptosis is involved in the development of SIMD. Resveratrol can upregulate miR-149, downregulate HMGB1, and inhibit ferroptosis pathway, thereby ameliorating LPS-induced endotoxemic cardiomyocyte injury (213). MiR-130b-3p mitigates septic cardiomyopathy by combating ferroptosis through the regulation of the AMPK/mTOR signaling pathway and directly targeting ACSL4 (214). Additionally, miR-31-5p alleviates sepsis-induced cardiomyopathy by inhibiting the deubiquitination of SLC7A11 via targeting BAP1, thereby also counteracting ferroptosis (215).

MiRNAs also play an important role in SIMD by regulating myocardial fibrosis and ferroptosis pathway (Table 5). Studies have shown that LPS induces the upregulation of plasmacytoma variant translocation 1 (PVT1) in myocardial fibroblasts. In turn, PVT1 inhibits the expression of miR-24 and upregulates Kruppel-like factor 6 (KLF6), ultimately inducing the proliferation and migration of myocardial fibroblasts (219). MiR-21-3p is overexpressed in cardiac fibroblasts and transferred to cardiomyocytes to induce SIMD, which is associated with elevated N-terminal brain natriuretic peptide and cardiac troponin (216). MiR-23b-mediated TGF-β1/Smad2/3 signaling promotes the differentiation of cardiac fibroblasts by inhibiting TGF-beta induced factor homeobox 1 (TGIF1). MiR-23b also promotes the deposition of extracellular matrix by inhibiting AKT/N-Cadherin signal transduction via PTEN, leading to myocardial fibrosis (217).

At present, miRNAs are regarded as the most promising biomarkers for differentiating SIMD from other myocardial injuries, primarily due to their stable existence in the body's circulatory system. As a result, numerous researchers have endeavored to screen out miRNAs that exhibit specific changes in the serum of patients with SIMD (Table 6). Studies have demonstrated that miR—497, cardiac troponin—I antigen (cTnI), fatty acid binding protein 3 (FABP3), and glycogen phosphorylase BB (GPBB) are elevated in the plasma of children with SIMD. The combination of these clinical indicators holds high diagnostic value, which is of great significance for the early diagnosis and treatment of pediatric SIMD (220). Moreover, miR—132 and miR—223 are negatively correlated with the activities of heart—type isoenzyme (CK—MB), cTnI, TNF—α, and IL—6 in serum, indicating their combined clinical value for the early diagnosis and prognosis assessment of SIMD (221). Additionally, miR—499a—5p also shows good diagnostic and prognostic value for SIMD (222).

In comparison with other potential biomarkers for SIMD, miRNAs have their unique advantages. Traditional biomarkers like cTnI and CK—MB have relatively low sensitivity and specificity in the early stage of SIMD. In contrast, miRNAs can be detected at an earlier stage and show more specific changes, enabling more accurate diagnosis. When it comes to diagnostic/therapeutic approaches, current methods mainly rely on clinical symptoms and traditional biomarker detection for diagnosis and drug—based therapies for treatment. The use of miRNAs not only provides a new perspective for diagnosis but also holds the potential for targeted therapy, which may offer more effective treatment options in the future.

Furthermore, inhibition of miR—29c—3p expression in animal models can reduce cardiac dysfunction and inflammation caused by sepsis, indicating its potential as a reliable biomarker for the diagnosis of sepsis (223). Reducing the expression level of miR—328 can improve cardiac dysfunction and inflammation in patients with sepsis, suggesting its role as a diagnostic indicator of sepsis (224). MiR—495 and the Sequential Organ Failure Assessment (SOFA) score are good diagnostic indicators for patients with SIMD, and overexpression of miR—495 can reduce inflammation and cardiac dysfunction caused by sepsis (225). In addition, miRNAs such as miR—21—3p, miR—155, miR—135a, miR—494—3p, and miR—223 in sepsis patients and miR—223, miR—495, miR—125b, miR—146, miR—135a, miR—495, miR—214, and miR—29b—3p in sepsis mice were identified as useful diagnostic markers for SIMD (226).