Research progress on programmed cell death of cardiomyocytes in pressure-overload hypertrophic cardiomyopathy

Abstract

Pressure overload hypertrophic cardiomyopathy (PO-HCM), a prevalent cardiovascular condition, is characterized by the heart’s adaptive response to chronic pressure overload. However, excessive pressure overload contributes to cardiomyocyte dysfunction and pathological hypertrophy. The pathological hallmarks of PO-HCM include the abnormal enlargement of cardiomyocytes (hypertrophy) and structural remodeling of myocardial tissue. The pathogenesis is multifaceted and involves hemodynamic alterations, imbalances in neurohumoral regulation, and intracellular signaling pathway abnormalities. Within this pathological context, programmed cell death is critically involved in cardiomyocytes. This review synthesizes current research on programmed cell death mechanisms in PO-HCM—including apoptosis, necroptosis, pyroptosis, autophagy, and ferroptosis—to inform translational research and guide future therapeutic development.

Introduction

Cardiovascular diseases represent a significant global health threat, with associated risks increasing due to the rapid pace of modern life and the aging population. Among these, PO-HCM has gained prominence as a notable manifestation of cardiovascular disease, especially given the increasing global prevalence of hypertension and associated conditions [1]. Severe hypertension, critical aortic stenosis, or aortic coarctation primarily cause PO-HCM by increasing the heart’s afterload [2, 3]. In response to this additional burden, cardiomyocytes undergo proliferation and hypertrophy to increase the pumping capacity of the heart. Although this adaptive hypertrophy initially supports cardiac function by enhancing sarcomeric contractile capacity and preserving stroke volume, persistent pressure overload eventually drives pathological remodeling. Pathological hypertrophy can lead to energy metabolism disorders in cardiomyocytes, cardiac fibrosis, cell death, or apoptosis, ultimately progressing to heart failure (HF) [4]. Consequently, pathological hypertrophy serves not only as a precursor to HF but also as an independent risk factor for numerous other cardiovascular diseases [1, 5]. Recent studies highlight that programmed cell death actively regulates the ^progression of PO-HCM, encompassing mechanisms such as apoptosis, necroptosis, autophagy, pyroptosis, and ferroptosis. Given the increasing recognition of programmed cell death in cardiovascular diseases, elucidating its specific role in the pathogenesis of PO-HCM and identifying potential therapeutic targets are essential for developing novel treatment strategies.

Pathogenesis of PO-HCM

In recent years, significant progress has clarified the pathogenesis of PO-HCM owing to advancements in molecular biology, cell biology, and signal transduction. The mechanisms involved are multifaceted and can be categorized into several key areas.

Hemodynamic factors

Hemodynamic factors are critical contributors to the development of PO-HCM [6]. When the heart is exposed to sustained or excessive pressure overload, cardiomyocytes initiate adaptive responses, such as hypertrophy and myocardial remodeling, to increase cardiac contractility and increase cardiac output, thereby meeting the heightened hemodynamic demands [7]. However, if pressure overload is excessive and prolonged, it can lead to cardiomyocyte damage and dysfunction, further exacerbating myocardial hypertrophy.

Neurohumoral regulation

Neurohumoral regulation is crucial in the pathogenesis of PO-HCM. When the heart experiences chronic pressure overload, the sympathetic nervous system is activated, leading to elevated levels of catecholamines such as adrenaline and noradrenaline [8]. Adrenaline binds to β1 receptors on cardiomyocyte membranes, enhancing myocardial contractility, increasing conduction velocity, elevating the heart rate, and boosting myocardial excitability. Noradrenaline, a potent α receptor agonist, also regulates β receptors. The activation of α receptors induces intense vasoconstriction, increasing blood pressure, whereas the activation of β receptors strengthens myocardial contraction and increases cardiac output. Prolonged overactivation of the sympathetic nervous system can lead to cardiomyocyte hypertrophy and interstitial fibrosis, thereby promoting the development of myocardial hypertrophy [9]. In addition to sympathetic activation, the renin-angiotensin-aldosterone system (RAAS) also centrally contributes to the pathogenesis of PO-HCM [10]. Angiotensin I (Ang I), an inactive precursor, undergoes conversion to the active form Angiotensin II (Ang II) by angiotensin-converting enzyme (ACE) [11]. The activation of the RAAS results in elevated levels of hormones such as Ang II and aldosterone, Ang II exerts its effects mainly through the Ang II type 1 receptor (AT1R) on cardiomyocytes and vascular smooth muscle cells [12]. Upon binding to AT1R, Ang II promotes vasoconstriction, leading to elevated afterload [10, 13]. Moreover, it stimulates cardiomyocyte hypertrophy and interstitial fibrosis by activating downstream signaling pathways such as Mitogen-activated protein kinase (MAPK) [14], Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) [15], and transforming growth factor beta (TGF-β) [16]. Ang II also induces oxidative stress, inflammation, and apoptosis in cardiomyocytes, further aggravating cardiac remodeling. These pathological changes contribute significantly to the progression of PO-HCM.

Cellular signal transduction

Cellular signal transduction is essential in the pathogenesis of PO-HCM. Research indicates that various signaling molecules and pathways, including the rat sarcoma (Ras) [17], extracellular signal-regulated kinase 1/2 (ERK1/2) [18, 19], phosphatidylinositol-3-kinase (PI3K/Akt) [20], MAPK [21], and signal transducer and activator of transcription (STAT) pathways [22] are critically involved in the onset and progression of myocardial hypertrophy. These signaling molecules directly influence the biological processes of cardiomyocyte growth, differentiation, and death, thereby modulating the progression of myocardial hypertrophy. Additionally, certain cytokines and growth factors, including nitric oxide [23, 24], endothelin [25, 26], TGF-β [27, 28], insulin-like growth factor-1 (IGF-1) [29], and calcium (Ca²⁺) [30], may also modulate cardiomyocyte gene expression and functional status, impacting the pathogenesis of PO-HCM.

Among these, Ca²⁺ serves as a critical second messenger in numerous cellular signaling pathways. Researchers have increasingly recognized abnormalities in Ca²⁺ signaling as contributors to the pathological remodeling of the myocardium under chronic pressure overload. Section 4.1.2.1.7 provides a detailed discussion of Ca²⁺-related molecular mechanisms.

Gene regulation

Gene regulation is a fundamental mechanism in the development and progression of PO-HCM. Under pressure overload, transcriptional reprogramming drives the hypertrophic response in cardiomyocytes through a network of transcription factors [31], microRNAs (miRNAs) [32], and epigenetic modifications [33].

Transcription factors

Mechanical stress and neurohumoral signals activate key transcription factors such as GATA binding protein 4 (GATA4) [34], nuclear factor of activated T-cells (NFAT) [6], and myocyte enhancer factor 2 (MEF2) [35]. These transcription factors orchestrate the expression of hypertrophy-associated genes, including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and β-myosin heavy chain (β-MHC). For instance, MAPK and calcineurin pathways can activate GATA4, which then directly enhances pro-hypertrophic gene expression [36].

MicroRNAs

MicroRNAs are a class of non-coding small RNAs that play crucial roles in regulating gene expression and cardiac remodeling. In PO-HCM, numerous microRNAs exhibit altered expression patterns and participate in critical biological processes such as cardiomyocyte growth, apoptosis, and stress response [37, 38]. These microRNAs modulate hypertrophic remodeling by targeting transcription factors, signaling intermediates, or metabolic regulators, exerting both pro-hypertrophic and anti-hypertrophic effects. Although researchers have identified many microRNAs associated with cardiac hypertrophy, their stage-specific expression, target specificity, and interactions with other regulatory mechanisms remain to be fully elucidated.

Epigenetic modifications

Epigenetic modifications—including DNA methylation and histone modifications—modulate chromatin accessibility and gene expression and play complex roles in the pathogenesis of PO-HCM [39, 40]. For example, DNA methylation of anti-apoptotic genes such as B-cell lymphoma 2 (Bcl-2) or forkhead box O3 (FOXO3) may reduce their expression, sensitizing cardiomyocytes to apoptosis [41], while hypomethylation of pro-apoptotic genes like B-cell lymphoma 2-associated X protein (Bax) or Caspase-9 enhances apoptotic pathways. In ferroptosis, histone deacetylation can repress antioxidant genes such as glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), thereby increasing lipid peroxidation and promoting cell death [42]. Similarly, histone methylation modifies the expression of necroptosis-related genes (e.g., receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL)) [43], while epigenetic suppression affects autophagy-related genes such as Beclin-1 and autophagy-related protein 5 (Atg5) in hypertrophic hearts [44]. Experimental studies demonstrate that Histone deacetylase (HDAC) inhibitors attenuate cardiac hypertrophy, underscoring the therapeutic potential of targeting epigenetic regulators [50]. These findings suggest that epigenetic profiles are integral in determining the susceptibility of cardiomyocytes to various forms of programmed cell death under pressure overload conditions.

Myocardial metabolism in PO-HCM

Energy metabolism in physiological States

Cardiomyocytes use various substrates, including fatty acids (FAs) and glucose, to generate the energy necessary for their normal functions through mitochondrial oxidative phosphorylation. During embryonic development, mammalian hearts primarily depend on glycolysis and lactate metabolism to produce ATP [46]. After birth, approximately 70% of ATP derives from fatty acid oxidation (FAO), with the remainder produced by the oxidation of glucose, lactate, ketone bodies, amino acids, and pyruvate [3].

Energy metabolism in PO-HCM

Changes in carbohydrate metabolism

Studies indicate that, under conditions of pressure overload, cardiomyocytes increase glucose uptake and increase glycolysis to meet their energy demands. However, excessive pressure can impair gluconeogenesis, leading to an energy metabolism imbalance that further exacerbates myocardial hypertrophy [47, 48].(Fig. 1).

Fig. 1.

Energy metabolism in PO-HCM. Abbreviations: BCAA, branched-chain amino acids; BCKA, branched-chain keto acids; CACT, carnitine/acylcarnitine translocase; CD36, fatty acid translocase / cluster of differentiation 36; CPT1/2, carnitine palmitoyltransferase 1/2; DHAP, dihydroxyacetone phosphate; FATP, fatty acid transport proteins; FFA, free fatty acid; GA3P, glyceraldehyde-3-phosphate; GLUT1/4, glucose transporter 1/4; GPX4, glutathione peroxidase 4; GSH, glutathione; GS-SG, oxidized glutathione; MPC, mitochondrial pyruvate carrier; NADP⁺, nicotinamide adenine dinucleotide phosphate; NADPH, nicotinamide adenine dinucleotide phosphate, reduced form; PEP, phosphoenolpyruvate; PPP, pentose phosphate pathway; PUFAs-OH, polyunsaturated fatty acids hydroxides; PUFAs-OOH, polyunsaturated fatty acids hydroperoxides; SLC1A5, solute carrier family 1 member 5; SLC3A2, solute carrier family 3 member 2; SLC7A5, solute carrier family 7 member 5; SLC7A11, solute carrier family 7 member 11; SLC25A44, solute carrier family 25 member 44; SLC38A1, solute carrier family 38 member 1; TCA Cycle, citric acid cycle; 3PG, 3-phosphoglycerate; α-KG, alpha-ketoglutarate

Enhanced glucose uptake

Early in the hypertrophic process, cardiomyocytes increase glucose uptake, typically through the upregulation of glucose transporter (GLUT) [49].

Enhanced glycolytic pathway

To satisfy elevated energy demands, cardiomyocytes increase glycolysis, breaking down glucose into pyruvate to generate ATP [50]. This increase is often accompanied by augmented activity of key glycolytic enzymes (such as hexokinase and phosphofructokinase) [51, 52]. Under hypoxic conditions, hypoxia-inducible factor-1α (HIF-1α) is activated [29], promoting the expression of glycolytic enzymes and further enhancing glycolysis.

Insulin resistance

As hypertrophy progresses, cardiomyocytes may develop insulin resistance, which reduces glucose utilization and exacerbates the energy supply‒demand imbalance [53].

Mitochondrial dysfunction

With increasing hypertrophy, mitochondrial dysfunction may arise, reducing the efficiency of oxidative phosphorylation and compelling cardiomyocytes to rely more heavily on glycolysis for energy [54, 55].

Changes in fatty acid metabolism

During the progression of PO-HCM, cardiomyocyte fatty acid metabolism undergoes complex changes. Normally, cardiomyocytes utilize fatty acids as a primary energy source through β-oxidation to maintain cardiac function [56]. In the early stages of hypertrophy, fatty acid metabolism may increase to meet heightened energy demands [57]. However, as hypertrophy progresses, dysregulation ensues (Fig. 1).

Decreased fatty acid uptake

As hypertrophy advances and relative hypoxia worsens, cardiomyocytes undergo metabolic reprogramming, favoring glycolysis over fatty acid oxidation for energy production [58]. This shift typically involves the downregulation of fatty acid transport proteins (such as CD36 molecule (CD36) and fatty acid transport protein (FATP)) [59].

Reduced fatty acid oxidation efficiency

Pressure overload inhibits enzymes like carnitine palmitoyltransferase 1 (CPT-1) and Acyl-CoA dehydrogenase(ACAD), impairing FA oxidation [60]. Chronic pressure overload can induce oxidative stress and inflammation, damaging the mitochondrial structure and function and thereby lowering fatty acid oxidation(FAO) rates [61]. The accumulation of incompletely oxidized fatty acid metabolites can lead to lipotoxicity, further inhibiting fatty acid oxidation. Additionally, myocardial hypertrophy may downregulate peroxisome proliferator-activated receptors (PPARs) that regulate FAO, thereby suppressing the expression of related genes [62].

Changes in amino acid metabolism

Amino acid metabolism also undergoes significant changes during the development of PO-HCM, typically involving elevated amino acid uptake and adjusted catabolism to meet heightened energy and biosynthesis demands (Fig. 1).

Enhanced amino acid uptake

Under prolonged pressure overload, cardiomyocytes increase amino acid uptake to satisfy energy and protein synthesis needs [63]. For example, cardiomyocytes may uptake more branched-chain amino acids (BCAAs), such as leucine, isoleucine, and valine, due to their critical roles in energy production and protein synthesis. This process typically involves enhanced activity of amino acid transport proteins, facilitating greater influx of amino acids from the bloodstream into the cells.

Enhanced amino acid metabolism

As hypertrophy progresses, cardiomyocytes adjust their amino acid catabolic pathways, particularly by increasing the metabolism of certain amino acids, such as glutamine and glutamate, as well as the catabolism of BCAAs [64]. These metabolic processes not only provide energy but also generate intermediates for ketone bodies and substrates for the tricarboxylic acid (TCA) cycle, supporting energy production. Certain amino acids, such as leucine, can activate the mTOR signaling pathway that critically regulates protein synthesis and promotes the development of myocardial hypertrophy.

Collectively, the dysregulation of glucose, fatty acid, and amino acid metabolism in PO-HCM leads to a common set of metabolic consequences. These include insufficient ATP production, accumulation of metabolic intermediates, and increased generation of reactive oxygen species (ROS), all of which contribute to oxidative stress. The resulting energy deficiency and oxidative damage disrupt mitochondrial function and promote pathological cardiac remodeling, ultimately accelerating disease progression.

Programmed cell death mechanisms in PO-HCM

Cell death, while the ultimate fate of all cells, also plays an indispensable role in the normal functioning and pathophysiology of the organism, much like cellular division and proliferation. Myocardial cell death is a primary contributor to cardiac dysfunction. Given that cardiomyocytes are highly specialized cells, their loss directly impacts the structure and function of the heart, accelerating the progression toward heart failure. Therefore, elucidating the mechanisms of cardiomyocyte death holds significant scientific and clinical importance.

In the context of PO-HCM, programmed cell death of cardiomyocytes encompasses various forms, including autophagy, ferroptosis, apoptosis, necroptosis, and pyroptosis (Fig. 2). These distinct modes of cell death collectively contribute to the progression from myocardial hypertrophy to heart failure. Understanding these mechanisms may provide insights into potential therapeutic targets for mitigating cardiac dysfunction associated with PO-HCM.

Fig. 2.

The programmed cell death in PO-HCM. In the context of PO-HCM, programmed cell death of cardiomyocytes encompasses various forms, including autophagy, ferroptosis, apoptosis, necroptosis, and pyroptosis

Autophagy

Autophagy is the process by which damaged, degenerated, or aged proteins and organelles are transported to lysosomes for degradation [65–67]. It is a ubiquitous physiological phenomenon that serves as a defensive mechanism. It helps cells respond to adverse conditions and participates in various disease pathologies. Moderate autophagy protects cells from environmental stress [68, 69]; however, excessive or insufficient autophagy can lead to disease [70, 71].

Formation process of autophagy

Researchers classify autophagy into three types based on how materials reach lysosomes: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA) [72]. The general term “autophagy” typically refers to macroautophagy. This process includes three major stages: autophagy induction, autophagosome formation, and autolysosome formation, followed by degradation of the autophagosome’s contents [73, 74].

Autophagy induction stage

When cells encounter starvation or other stress conditions, intracellular energy-sensing mechanisms become activated [75]. One of the most well-known signaling pathways involved is the AMP-activated protein kinase (AMPK) pathway. The activation of AMPK leads to the phosphorylation of the ULK1–Atg13–Atg101–FIP200 (RB1CC1) complex, a critical step for initiating autophagy [76]. Subsequently, the phosphatidylinositol 3-kinase (Class III PI3K)–Beclin-1–VPS34 complex activates and localizes to organelle surfaces, such as mitochondria and the endoplasmic reticulum, to promote isolation membrane formation, which gives rise to the autophagosome [77].

Autophagosome formation stage

At this stage, autophagy-related proteins (Atgs), including Atg7, Atg10, Atg12, Atg5, and Atg16, become activated and drive autophagosome construction. Atg12 conjugates with Atg5 to form a functional complex that includes Atg16, which is crucial for the elongation and closure of the autophagosome [78]. Meanwhile, Atg4 converts microtubule-associated protein light chain 3 (LC3) to LC3-I, and Atg7 and Atg3 convert it to LC3-II, which binds to the isolation membrane and participates in autophagosome formation [79].

Autolysosome formation and degradation stage

The autophagosome fuses with the lysosome to form the autolysosome, marking the culmination of the autophagy process. Hydrolytic enzymes within the autolysosome degrade the autophagosomal contents. This process facilitates the recycling of amino acids, lipids, and other small molecules for cellular reuse [80–82].

Molecular mechanisms of autophagy in PO-HCM

Cardiomyocytes, being highly differentiated and having limited regenerative capacity, rely on autophagy to maintain myocardial health. Moderate autophagy removes damaged proteins and organelles, thus preventing dysfunction [83]. However, an imbalance in autophagy—either excessive or insufficient—can contribute to cardiac diseases [84].

In the context of PO-HCM, the role of autophagy is particularly complex [85–87]. Some studies indicate that autophagy counteracts myocardial hypertrophy by promoting protein degradation, while decreased autophagy may worsen hypertrophy [68, 87, 88]. Conversely, other evidence suggests that pressure overload induces autophagy and that autophagy levels may reflect hypertrophy severity [68, 71, 85, 89–91]. Thus, the exact role of autophagy in myocardial hypertrophy may depend on its level and the different stages of hypertrophy development (Fig. 3).

Fig. 3.

The molecular mechanisms of autophagy in PO-HCM. Autophagy can be divided into three stages: the induction stage, the formation stage of autophagosomes, and the formation of autophagic lysosomes and the degradation of their contents. Abbreviations: AMPK, 5’-AMP-activated protein kinase; Atgs, autophagy-related proteins; Bcl-2, B-cell lymphoma 2; ERK, extracellular signal-regulated kinase; FIP200, focal adhesion kinase family interacting protein of 200 kDa; G6P, Glucose-6-Phosphate; LC3, microtubule-associated protein light chain 3; Mfn1/2, Mitofusin 1/2; MiRNA, MicroRNA; mTORC1, Mechanistic Target of Rapamycin Complex 1; NO, nitric oxide; PINK1, PTEN-induced kinase 1; PI3K/AKT, phosphatidylinositol 3-kinase/Akt signaling pathway; ULK1, Unc-51-like autophagy-activating kinase 1; UVRAG, UV radiation resistance associated; VDAC1, Voltage-Dependent Anion Channel 1; Vps15, vacuolar protein sorting 15; ΔΨm, mitochondrial membrane potential

Moreover, excessive autophagy may not simply result from increased autophagosome formation, but also from impaired lysosomal degradation, leading to autophagosome accumulation and insufficient clearance of cellular debris. Studies have shown [71, 74] that under pressure overload conditions, autophagic flux may be disrupted, with elevated LC3-II levels and sequestome 1 (p62) accumulation serving as hallmarks of autophagy arrest. These changes exacerbate cellular stress and dysfunction, illustrating how disrupted autophagy contributes pathologically to PO-HCM.

MicroRNA

MicroRNAs are a class of endogenous noncoding small RNAs that influence various biological processes by regulating the expression of target genes [92]. Numerous studies have indicated that several miRNAs, such as the miR-212/132 family, miR-30, miR-199a, and miR-34c-5p, participate in the regulation of cardiac hypertrophy and autophagy. Ucar et al. reported that the miR-212/132 family regulates cardiac hypertrophy and autophagy by targeting FOXO3 [37]. Administering specific miR-132 can alleviate PO-HCM in mice [37]. In patients with cardiac hypertrophy, the serum levels of miR-30 are upregulated, and treatment with miR-30a mimics can reduce the upregulation of hypertrophy-related genes induced by Ang II. Furthermore, circulating miR-30 levels are positively correlated with left ventricular wall thickness, potentially serving as an important marker for diagnosing hypertrophy associated with excessive autophagy [37]. In a mouse model of PO-HCM, researchers observed that miR-199a expression was upregulated in the left ventricular tissue. MiR-199a suppresses autophagy by activating the mTOR pathway, thereby contributing to cardiac hypertrophy [38]. Additionally, the overexpression of miR-199a can activate mTOR through glycogen synthase kinase 3 beta (GSK3β), thus further inhibiting cardiac autophagy [38]. Other studies have shown that miR-34c-5p can decrease Atg4B expression and reduce autophagic flux, thereby mediating the occurrence of cardiac hypertrophy^[194].

mTOR

mTOR is a highly conserved serine/threonine protein kinase that functions as a potent negative regulator of autophagy [65, 67, 94, 95], serving as a primary molecular switch to inhibit this process [37]. Activated mTOR inhibits autophagy by suppressing the phosphorylation of the Unc-51-like kinase 1 (ULK1)–Atg13–Atg101–focal adhesion kinase family interacting protein of 200 kDa (FIP200) complex [96–98]. mTOR exists in two distinct protein complexes, mTORC1 and mTORC2 [99]. mTORC1, which is composed of mTOR, Raptor, and mammalian lethal with Sect. 13 protein 8 (mLST8), is sensitive to rapamycin and primarily regulates the transcription and translation processes involved in cell growth and autophagy [100]. In contrast, mTORC2, which is composed of mTOR, Rictor, mLST8, and Protor, is insensitive to rapamycin and is involved primarily in cytoskeletal regulation and cell growth [101]. Studies indicate that mTORC1 is activated during both physiological cardiac hypertrophy (such as exercise training) and pathological cardiac hypertrophy (such as aortic constriction and spontaneous hypertension). When cardiac function deteriorates and heart failure develops, mTORC1 activity declines [102, 103]. In the context of cardiac hypertrophy, the PI3K/Akt pathway is a central regulator of activating mTORC1 [104–106], along with β-adrenergic signaling, the ERK pathway, and nitric oxide signaling [107–109]. Additionally, under conditions of pressure overload, biomechanical activation of transient receptor potential channels and adhesion kinases promotes mTORC1 activation [110, 111], whereas the accumulation of glucose-6-phosphate aids in activating mTORC1 in the hypertrophic myocardium resulting from pressure overload. mTORC1 inhibits autophagy initiation by reducing the activity of the ULK1–Atg13–Atg101–FIP200 complex through the suppression of ULK1 phosphorylation and its interaction with Atg13 [112], as well as by inhibiting Atg7 expression [113–117]. Clinical studies have shown that inhibiting mTORC1 can activate autophagy, significantly alleviating left ventricular hypertrophy caused by thyroid hormones [118] or hypertension [119] and improving left ventricular function [120]. Nutritional starvation or rapamycin intervention can significantly inhibit mTORC1, increase ULK1 phosphorylation, increase the activity of the ULK1–Atg13–Atg101–FIP200 complex, and promote its interaction with AMPK, thus activating autophagy [65, 67, 94, 95, 121, 122].

5’-AMP-activated protein kinase (AMPK)

AMPK, a serine/threonine protein kinase and a key sensor of cellular energy status, promotes autophagy and regulates cardiac hypertrophy [123]. In a transverse aortic constriction (TAC) mouse model, Li et al. found that left ventricular cardiomyocytes exhibited suppressed autophagy [123]. The administration of AMPK activators such as 5-aminoimidazole-4-carboxamide-1-β-d-ribonucleoside (AICAR) or metformin can upregulate AMPK expression, inhibit mTORC1 activity [124], and activate autophagy in cardiomyocytes, thereby inhibiting cardiac hypertrophy. Moreover, the administration of mTORC1 inhibitors such as rapamycin directly upregulates autophagy, achieving similar results [125]. These results support the role of the AMPK/mTOR axis in regulating autophagy in pressure overload-induced hypertrophy.

Unc-51-like autophagy-activating kinase 1 (ULK1)

ULK1 is a serine/threonine protein kinase that participates in the regulation of autophagy in mammals [126]. ULK1 is a critical molecule for initiating autophagy and is part of a multiprotein complex known as the ULK1 complex, which includes ULK1, Atg13, FIP200 (RB1CC1), and Atg101 [127]. When cells experience starvation or other stress conditions, the ULK1 complex is activated, leading to the initiation of autophagy. mTORC1 and AMPK are the primary upstream kinases that regulate the activity of the ULK1 complex. Research has indicated that mTORC1 is activated in mouse models of cardiac hypertrophy induced by TAC [128]. mTORC1 inactivates ULK1 by phosphorylating it at Ser757, thereby inhibiting autophagy [129–131]. AMPK indirectly activates ULK1 by inhibiting mTORC1 [132], and it can also directly phosphorylate multiple sites on ULK1 (including Ser317, Ser467, Ser555, Thr574, Ser637, and Ser777) to activate ULK1 independently of mTORC1 inhibition, thereby promoting autophagy and inhibiting cardiac hypertrophy [98].

Class III PI3K-Beclin-1 pathway

Beclin-1, an ortholog of the autophagy-related protein Atg6/Vps30, participates in the formation of the class III PI3K complex, mediating the localization of autophagy-related proteins to phagophores and regulating autophagy by inducing the formation of double-membrane autophagosomes, thus is a central regulator of the induction and maturation of autophagosomes [133]. Typically, beclin-1 is in an inhibited state and binds to the Bcl-2 protein [134]. Under normal conditions, Bcl-2 binds to and inhibits Beclin-1. During pressure overload, the Beclin-1–Bcl-2 interaction weakens, which frees Beclin-1 and allows it to activate autophagy. Some studies suggest that the autophagic process activated by Beclin-1 in cardiac hypertrophy may result in impaired clearance of autophagosomes, leading to cell death [135]. The activation of class III PI3Ks promotes the initial aggregation of phagophores, marking the initial steps in autophagosome formation.

PINK1-Parkin pathway

In normal mitochondria, PTEN-induced kinase 1 (PINK1) is transported to mitochondria via its mitochondrial targeting sequence and is degraded by mitochondrial processing peptidase (MPP) upon entry into the mitochondria, followed by further cleavage by the inner mitochondrial protease presenilin associated rhomboid-like (PARL) [136]. The cleaved PINK1 is then exported to the cytoplasm for degradation by the proteasome. However, under prolonged pressure overload leading to cardiac hypertrophy, the mitochondrial membrane potential (MMP, ΔΨm) is compromised, preventing the full entry of PINK1 into the inner mitochondrial space and leading to its stable accumulation on the outer mitochondrial membrane [137]. Accumulated PINK1 recruits and phosphorylates Parkin, an E3 ubiquitin ligase, which in turn ubiquitinates outer mitochondrial membrane proteins such as VDAC1 and Mfn1/2. LC3 recognizes these ubiquitinated proteins and mediates their recruitment into autophagosomes. These autophagosomes fuse with lysosomes to form autolysosomes, where the damaged mitochondria undergo degradation [138].

Ca²⁺

Intracellular Ca²⁺ are important regulators of autophagy [139]. Store-operated Ca²⁺ entry (SOCE) is one of the primary pathways for increasing intracellular Ca²⁺ concentrations. The key components of SOCE include stromal interaction molecule 1 (STIM1) and Ca²⁺ release-activated Ca²⁺ channel protein (Orai1) [140]. Although both SOCE and excessive autophagy are considered major pathological factors in cardiac hypertrophy, the specific relationship between these processes remains unclear. Some studies suggest that excessive autophagy can contribute to pathological cardiac hypertrophy induced by Ang II. Cytoplasmic Ca²⁺ signaling is closely linked to the regulation of autophagy, and SOCE, as a major pathway for Ca²⁺ entry into cells, plays a significant role in regulating intracellular Ca²⁺ levels and autophagy in cardiomyocytes through its key factors, STIM1 and Orai1 [141].

In addition to SOCE, inositol 1,4,5-trisphosphate receptors (IP3Rs), located on the membrane of the sarcoplasmic/endoplasmic reticulum, are also critical regulators of intracellular Ca²⁺ dynamics. Upon activation by IP3, IP3Rs mediate Ca²⁺ release into the cytosol [142]. This signaling pathway has been implicated in cardiomyocyte hypertrophy, apoptosis, and autophagy regulation. Moreover, Ca²⁺-induced Ca²⁺ release (CICR) through RyRs and IP3Rs can result in mitochondrial Ca²⁺ overload, exacerbating oxidative stress and activating apoptotic and necroptotic pathways—particularly under sustained pressure overload conditions in PO-HCM. Dysregulation of Ca²⁺-handling proteins such as SERCA and the Na⁺/Ca²⁺ exchanger (NCX) further contributes to cytosolic Ca²⁺ overload and contractile dysfunction.

Thus, both SOCE and IP3R-mediated Ca²⁺ release represent key pathways linking Ca²⁺ signaling to autophagy and cardiomyocyte fate in PO-HCM. While autophagy primarily regulates the degradation of damaged organelles and proteins, the failure of this mechanism can also lead to oxidative stress and lipid dysregulation, bridging a pathological link to ferroptosis.

Potential therapeutic strategies

In managing PO-HCM, pharmacological interventions such as mTOR inhibitors and antioxidants may offer potential therapeutic benefits. These agents can enhance cardiomyocyte autophagy by modulating autophagosome formation, lysosomal function, and overall autophagic flux (Table 1). Additionally, lifestyle modifications—including increased physical activity and reduced smoking—may help lower oxidative stress and inflammation, thereby improving autophagic activity in cardiomyocytes. During PO-HCM, the autophagic process in cardiomyocytes involves complex molecular mechanisms and regulatory factors. It is important to distinguish between basal autophagy and stress-induced autophagy, as they play different roles. Basal autophagy maintains cellular homeostasis under normal conditions by clearing damaged proteins and organelles, thus exerting cardioprotective effects. In contrast, excessive or dysregulated stress-induced autophagy—triggered by pathological stimuli such as pressure overload—can contribute to maladaptive cardiac remodeling and cardiomyocyte death.

Table 1.

Role of small-molecule drugs in the treatment of autophagy in cardiomyopathy

Compound	Mechanism of action	Effect on autophagic signaling	Clinical Phase	References
AICAR and metformin	AMPK activation, mTORC1 inactivation	Activate of autophagy	Preclinical	[123]
Berberine	AMPK activation, mTORC1 inactivation, Inhibition of ERK1/2 and p38	Activate of autophagy	Preclinical	[143–145]
Cinacalcet	AMPK activation	Activate of autophagy	Preclinical	[146]
Curcumin	mTORC1 inactivation	Activate of autophagy	Preclinical	[147]
Dihydromyricetin	AMPK/ULK1 activation	Activate of autophagy	Preclinical	[145]
Empagliflozin	Inhibition of mTOR/p-ULK1	Activate of autophagy	Preclinical	[148]
HUCMSC-EXO	Inhibition of AMPK-ULK1	Inhibit excessive autophagy	Preclinical	[149]
H2S	AMPK/ mTOR activation	Activate of autophagy	Preclinical	[150]
Isoginkgetin	AMPK activation, mTORC1 inactivation	Activate of autophagy	Preclinical	[151]
Irisin	PI3K/Akt activation	Inhibition of autophagy	Preclinical	[152]
Liraglutide	AMPK/ mTOR activation	Increase autophagy flux	Preclinical	[153]
Metformin	AMPK/ mTOR activation	Activate of autophagy	Preclinical	[154, 155]
Puerarin	AMPK activation, mTORC1 inactivation	Activate of autophagy	Preclinical	[156]
Qiliqiangxin Capsules	Inhibition of LC3 expression, anti-inflammatory	Inhibition of autophagy	Preclinical	[157, 158]
Rapamycin or its analogs	Activation of cAMP/PKA, MAPK/ERK1/2 and MEK/ERK/ Beclin-1; Inhibition of mTORC1	Activate of autophagy	Preclinical	[120, 159–162]
Sirolimus, Everolimus	mTORC1 inhibition	Activate of autophagy	Clinical	[163–166]
Platycodin D	AMPK activation	Activate of autophagy	Preclinical	[167]
R118	AMPK activation	Activate of autophagy	Preclinical	[168]
Resveratrol	Activate of AMPK/ mTOR	Increase autophagy flux	Preclinical	[169]
SO2	PI3K/Akt inhibition	Activate of autophagy	Preclinical	[170]
Trimetazidine	Activation PI3K/Akt and AMPK	Activate of autophagy	Preclinical	[171]

Therefore, therapeutic strategies should aim to fine-tune autophagic activity: enhancing basal autophagy to preserve myocardial integrity while preventing the excessive accumulation of autophagosomes due to impaired lysosomal clearance. Pharmacological agents such as metformin, AICAR, and rapamycin have been shown to regulate autophagy via AMPK or mTOR pathways, though their effects may vary depending on the physiological versus stress-induced context. Further research is needed to deepen our understanding of PO-HCM pathogenesis and to support the development of effective therapeutic strategies. Combining pharmacological therapies with lifestyle interventions may help enhance cardiomyocyte autophagy and improve patient outcomes.

Ferroptosis

Ferroptosis represents a newly recognized form of iron-dependent programmed cell death. This process disrupts intracellular lipid peroxide metabolism through iron-catalyzed reactions. When the cellular antioxidant capacity decreases and ROS accumulate, redox imbalance occurs, ultimately triggering cell death [172, 173].

Ferroptosis process

The cystine/glutamate inverse transporter (System XC-) is a Na⁺-dependent amino acid inverse transporter, a heterodimer comprising light-chain SLC7A11 and heavy-chain SLC3A2 [174]. This system is ubiquitously present in the phospholipid bilayers of biological cells [175, 176] and exchanges a molecule of cystine for a molecule of glutamate [177–179]. Inside the cell, cystine is reduced to cysteine and synthesized into glutathione (GSH) by γ-glutamylcysteine synthetase and glutathione synthetase, and GSH is essential for combating oxidative stress, mitigating lipid peroxidation, and protecting tissues and cells [180, 181]. GPX4 is the sole enzyme in the body capable of efficiently reducing lipid peroxidation in biological membranes [182]. When System Xc − function becomes impaired, cells cannot import cystine efficiently, leading to glutamate accumulation, GSH depletion, and decreased GPX4 activity. As a result, lipid peroxides accumulate and undergo further iron-catalyzed oxidation via Fe²⁺, generating ROS and lipid radicals [183, 184]. These events not only damage the cell and plasma membranes but also induce the formation of protein pores in the cell membrane, disrupting intracellular homeostasis [185, 186]. Additionally, lipid radicals attack lipid structures within membranes, generating toxic byproducts such as malondialdehyde and 4-hydroxynonenal. These molecules amplify membrane damage and induce irreversible structural and functional deterioration, culminating in ferroptosis [187].

Molecular mechanisms of ferroptosis in PO-HCM

Recent studies have increasingly demonstrated that ferroptosis is vital to the occurrence and development of PO-HCM [188–190]. Under pressure overload, cardiomyocytes show enhanced ferroptotic activity, which leads to cell death and functional impairment [188, 191, 192] (Fig. 4).

Fig. 4.

The molecular mechanisms of ferroptosis in PO-HCM. Abbreviations: Alox15, arachidonate 15-lipoxygenase; ATF4, activating transcription factor 4; Atgs, autophagy-related proteins; DMT1, divalent metal transporter 1; FPN1, Ferroportin 1; GPX4, glutathione peroxidase 4; GLUT1/4, glucose transporter 1/4; GSH, glutathione; GS-SG, oxidized glutathione; HO-1, heme oxygenase-1; IREB2, iron responsive element binding protein 2; Keap1, kelch-like ech-associated protein 1; mTORC1, mechanistic target of rapamycin complex 1; NADPH, nicotinamide adenine dinucleotide phosphate, reduced form; NCOA4, nuclear receptor coactivator 4; NOX4, NADPH oxidase 4; Nrf2, nuclear factor erythroid 2-related factor 2; P53, tumor protein p53; P62, sequestosome 1; PPP, pentose phosphate pathway; PUFAs-OH, polyunsaturated fatty acids hydroxides; PUFAs-OOH, polyunsaturated fatty acids hydroperoxides; ROS, reactive oxygen species; SAT1, spermidine/spermine N1-acetyltransferase 1; SLC1A5, solute carrier family 1 member 5; SLC3A2, solute carrier family 3 member 2; SLC7A11, solute carrier family 7 member 11; SLC38A1 solute carrier family 38 member 1; STEAP3, six-transmembrane epithelial antigen of prostate 3; TF, transcription factor; TFR1, transferrin receptor protein 1; ZIP8/14, zinc-regulated transporter, iron-regulated transporter-like protein 8/14

Iron metabolism and lipid peroxidation

Abnormal iron metabolism in cardiomyocytes under pressure overload may lead to localized increases in labile intracellular iron, which catalyzes Fenton reactions and promotes the generation of ROS, including hydroxyl radicals. These ROS exacerbate lipid peroxidation and generate toxic lipid peroxides that compromise membrane integrity, thereby promoting ferroptosis [194]. At the same time, antioxidant defenses—such as GSH and GPX4—become depleted, which weakens the cell’s ability to clear lipid peroxides [194]. It is important to note, however, that this ferroptosis in PO-HCM reflects a local redox imbalance rather than systemic iron overload. In contrast, iron overload cardiomyopathy (IOC), which arises in transfusional iron loading or hereditary hemochromatosis, is primarily linked to arrhythmia, restrictive, or dilated cardiomyopathy, not hypertrophy [195]. Therefore, ferroptosis in PO-HCM should be viewed as a secondary stress-driven cell death mechanism, distinct from the pathogenesis of classical IOC.

Dysregulation of the antioxidant defense system

The antioxidant defense system, which includes GSH, superoxide dismutase (SOD), and catalase, neutralizes free radicals and inhibits lipid peroxidation [196]. When this system is disrupted, particularly with reduced GSH levels, cells become less capable of clearing free radicals and lipid peroxides, leading to exacerbated lipid peroxidation. These lipid peroxides further damage cell membranes, thereby promoting ferroptosis. Furthermore, dysregulation of antioxidant defense may aggravate iron accumulation, as iron catalyzes elevated free radical generation in oxidative environments [197, 198]. Overall, this dysregulation enhances iron-dependent oxidative damage, thereby promoting ferroptosis and accelerating the pathological progression of cardiac hypertrophy.

Nrf2/ARE pathway

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial transcription factor that is activated under oxidative stress; Nrf2 enters the nucleus to bind to antioxidant response elements (AREs) and initiate the transcription of antioxidant genes such as glutathione synthetase and ferritin [199]. By doing so, Nrf2 increases antioxidant capacity, suppresses lipid peroxidation, and protects against ferroptosis. Nrf2 also promotes iron storage and upregulates SLC7A11(a component of the System Xc- transporter) to enhance cystine uptake [200–202]. However, sustained oxidative stress during pressure overload may impair Nrf2 activity. This dysfunction leads to excess iron accumulation, excessive ROS production, and enhanced ferroptosis [203].

p53 signaling pathway

p53 promotes ferroptosis by increasing TFR1 expression and inhibiting ferritin, which raises free iron concentrations and boosts ROS production [204]. Additionally, p53 downregulates antioxidant enzymes, such as glutathione synthetase, which weakens oxidative defenses and facilitates ferroptosis [177]. Therefore, maintaining a balanced p53 response is essential to prevent ferroptosis under hypertrophic stress.

mTOR signaling pathway

The mTOR pathway promotes cell growth and inhibits autophagy [205]. Overactivation of mTOR suppresses autophagy, reducing the clearance of iron and lipid peroxides, thereby accelerating ferroptosis. By regulating mTOR activity, researchers can restore autophagy, reduce intracellular iron levels, and limit lipid peroxidation, thus slowing ferroptosis in PO-HCM [102].

System Xc-

System Xc- is responsible for transporting extracellular cysteine, which is a critical precursor for synthesizing GSH, into cells [206]. Under pressure overload conditions, the function of System Xc- may be impaired, leading to decreased intracellular cysteine and GSH levels, thereby weakening antioxidant defenses and increasing lipid peroxidation and iron-dependent oxidative damage [207]. This imbalance exacerbates ferroptosis, promoting cardiomyocyte injury and the progression of hypertrophy.

NOX4 signaling pathway

NADPH oxidase 4 (NOX4) generates ROS [208]. Under pressure overload, cardiomyocytes activate NOX4, which significantly elevates ROS levels. These ROS promote lipid peroxidation in cell membranes, forming harmful lipid peroxides and disrupting cellular iron metabolism, thereby increasing the number of intracellular free iron ions, which further catalyze lipid peroxidation and aggravate ferroptosis.

ATF4 signaling pathway

Activating transcription factor 4 (ATF4) is a key transcription factor involved in adaptive cellular responses to stress [209]. Pressure overload upregulates ATF4 expression, which activates downstream genes involved in oxidative stress and metabolism [210]. The activation of ATF4 can inhibit antioxidant defenses and disrupt iron metabolism, thereby increasing the intracellular free iron concentration. Elevated free iron levels promote lipid peroxidation, leading to the formation of harmful lipid peroxides and triggering ferroptosis [211]. Thus, the ATF4 signaling pathway exacerbates cardiac dysfunction by increasing oxidative stress and interfering with iron metabolism.

Iron homeostasis regulatory factors

Iron homeostasis regulatory factors (such as iron regulatory protein-1 (IRP-1) and IRP-2 influence ferroptosis by regulating cellular iron accumulation and utilization [212]. These factors adjust the expression of TFR1 and ferritin in response to unstable intracellular iron levels, thereby controlling iron intake and storage. Under pressure overload, cardiomyocytes may experience excessive iron accumulation due to dysregulation of these factors, resulting in elevated free iron concentrations. Excess free iron catalyzes the Fenton reaction, producing harmful oxidants such as hydroxyl radicals, exacerbating lipid peroxidation and promoting ferroptosis [213].

While ferroptosis is implicated in myocardial injury during PO-HCM, its precise role in disease progression remains to be clarified. It is currently unclear whether ferroptosis serves as a causative mechanism driving cardiomyocyte death or is rather an epiphenomenon that arises secondary to chronic oxidative stress and iron dysregulation, particularly in the advanced stages of hypertrophy. The accumulation of lipid peroxides and the reduction of protective factors like GPX4 may reflect a maladaptive response to prolonged metabolic stress rather than a primary initiating event. Therefore, further temporal and mechanistic studies are necessary to define the exact role of ferroptosis in PO-HCM pathogenesis.

Beyond lipid peroxidation and iron overload, ferroptosis may influence apoptotic signaling through ROS accumulation and mitochondrial injury, highlighting shared stress pathways between these cell death forms.

Potential therapeutic strategies

For patients with PO-HCM, pharmacological treatments such as antioxidants and iron chelators may offer potential therapeutic benefits. These drugs can increase the antioxidant capacity of cardiomyocytes and reduce iron accumulation, thereby lowering the risk of ferroptosis (Table 2). Additionally, modifying lifestyle factors—such as increasing physical activity and reducing smoking—can help decrease oxidative stress and inflammation levels, thereby further lowering the risk of ferroptosis in cardiomyocytes.

Table 2.

Role of small-molecule drugs in the treatment of ferroptosis in cardiomyopathy

Compound	Mechanism of action	Effect on ferroptotic signaling	Clinical Phase	References
Dexrazoxane	Inhibits iron overload	Inhibition of ferroptosis	Preclinical	[188, 191]
Deferoxamine	Inhibits iron overload	Inhibition of ferroptosis	Preclinical	[214, 215]
Deferiprone	Inhibits iron overload	Inhibition of ferroptosis	Preclinical	[191]
Losartan	Inhibits iron overload, reduces lipid peroxidation and improves antioxidant capacity	Inhibition of ferroptosis	Preclinical	[216]
Puerarin	Inhibits iron overload and lipids peroxidation	Inhibition of ferroptosis	Preclinical	[217]
UAMC-3203	Inhibits lipid peroxidation	Inhibition of ferroptosis	Clinical	[218]
DHA	Increase IRF3-SLC7A11, decrease ALOX12 and iron levels, antioxidant, regulates iron metabolism and lipid metabolism	Activate of ferroptosis	Preclinical/ Clinical	[219, 220]
ENPP2	Reduce ROS generation caused by erastin	Inhibition of ferroptosis	Preclinical	[221]
Ferrostatin-1	Inhibits lipids peroxidation, stabilizes cell membranes, reduces cellular damage, improves cardiac function, and anti- inflammatory effects	Inhibition of ferroptosis	Preclinical	[222]
Dexmedetomidine	Activates GPX4	Inhibition of ferroptosis	Preclinical	[223]
Liproxstatin 1	Increase GPX4 protein levels and reduce ROS generation	Inhibition of ferroptosis	Preclinical	[224–226]
miR-351	Regulate the JNK/p53 signalling pathway	Inhibition of ferroptosis	Preclinical	[192]
mTOR	Cellular iron transport and reduce ROS production	Inhibition of ferroptosis	Preclinical	[227]
MitoTEMPO	Scavenge lipid peroxidation specifically in the mitochondria	Inhibition of ferroptosis	Preclinical	[188]

The ferroptosis process in PO-HCM is complex and involves multiple molecular mechanisms and influencing factors. Continued research will deepen the understanding of PO-HCM pathogenesis and support the development of effective treatment strategies. A comprehensive approach combining antioxidant therapies, iron chelation, mitochondrial protection, and lifestyle modifications may help mitigate ferroptosis in cardiomyocytes and improve patient outcomes.

Apoptosis

Apoptosis is a form of programmed cell death that occurs in response to internal and external signals [228]. Unlike necrosis, apoptosis is a highly ordered and precise process characterized by specific morphological changes, such as cell shrinkage, nuclear condensation, and fragmentation of the cytoplasm and nuclear membranes, along with DNA degradation. Apoptosis is a major contributor to regulating cell numbers and maintaining normal tissue structure. It is vital for processes such as embryonic development, immune regulation, and tissue repair. The apoptotic process can be divided into two pathways: the extrinsic pathway and the intrinsic pathway [229]. The extrinsic pathway is mediated by death receptor family proteins on the cell membrane, whereas the intrinsic pathway is activated by various stimuli, including intracellular damage and oncogenic stress, leading to mitochondria-dependent apoptosis [230].

Mechanisms of apoptosis in PO-HCM

Recent studies have increasingly demonstrated that apoptosis is a major contributor to the occurrence and development of PO-HCM [231, 232]. Under pressure overload, the apoptotic process in cardiomyocytes may be enhanced, leading to cell death and functional impairment (Fig. 5).

Fig. 5.

The molecular mechanisms of apoptosis in PO-HCM. Abbreviations: Ang II, angiotensin II; AP-1, activator protein-1; Apaf-1, apoptotic protease activating factor-1; ASK1, apoptosis signal-regulating kinase 1; AT1, angiotensin II type 1 receptor; ATF-2, activating transcription factor 2; Bax, Bcl-2-associated X protein; Bcl-2, B-cell lymphoma-2; c-Jun, jun proto-oncogene, AP-1 transcription factor subunit; Cytc, cytochrome c; ER stress, endoplasmic reticulum stress; Fas, fas cell surface death receptor; gp130, glycoprotein 130; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; mPTP, mitochondrial permeability transition pore; P38, p38 mitogen-activated protein kinase; RAAS, renin-angiotensin-aldosterone system; Ros, reactive oxygen species; Trailr, TNF-related apoptosis-inducing ligand receptor; TNF-α, tumor necrosis factor-alpha; ΔΨm, mitochondrial membrane potential

Mechanical strain and oxidative stress

In PO-HCM, the left ventricle faces elevated afterload, causing prolonged excessive strain on the myocardium. This condition, combined with the high energy demands of the heart and heightened wall tension, leads to intensified oxidative metabolism and amplifies oxidative stress levels. Elevated oxidative stress can trigger the activation of c-Jun N-terminal kinase (JNK), a member of the stress-activated protein kinase family [233]. This activation then leads to the activation of c-Jun and activating transcription factor 2 (ATF-2), contributing to both cell hypertrophy and apoptosis [234]. Studies have demonstrated that mechanical strain can result in peroxide accumulation and upregulate expression of Fas protein, promoting cardiomyocyte apoptosis within a short period of time [235].

Neurohumoral factors

A hallmark of hypertension is the activation of the systemic and local RAAS, which is critically implicated in PO-HCM. Ang II, which acts as a pivotal effector molecule within the RAAS, profoundly modulates cardiomyocyte apoptosis. By binding to its AT1 receptor, Ang II initiates a series of intricate responses [236], such as decreasing the Bcl-2/Bax ratio, activating p38 MAPK, triggering caspase-3 activity, and inducing DNA fragmentation, all of which contribute to the apoptosis of cardiomyocytes [237].

Cytokines

Several cytokines regulate cardiomyocyte apoptosis in PO-HCM. Specifically, tumor necrosis factor-alpha (TNF-α) has been demonstrated to induce apoptosis in cardiomyocytes [238]. Within the setting of hypertension, the activation of the renin‒angiotensin system by Ang II can substantially increase TNF-α expression at both the mRNA and protein levels [239].

Transcription factors

The transcription factor GATA4 plays a central role in regulating cardiomyocyte survival and apoptosis [240]. As an important regulator of cardiomyocyte growth and differentiation, GATA4 oversees the expression of many genes linked with hypertrophy, which often include GATA regulatory sequences in their promoters [241]. Elevated expression of GATA4 or GATA6, another member of the GATA family, can induce hypertrophic effects in cultured cardiomyocytes and in transgenic mouse models [242].

Glycoprotein 130 (gp130) signaling pathway

Gp130 enhances cardiomyocyte survival and inhibits apoptosis through its downstream signaling cascade [243, 244]. In mechanical overload models, deletion of gp130 induces extensive cardiomyocyte apoptosis and accelerates left ventricular hypertrophy [32, 245]. Conversely, overexpressing gp130 in hypertensive mouse hearts correlates with reduced apoptosis, suggesting a protective role [246].

Apoptosis signal-regulating kinase 1 (ASK1)

ASK1 mediates Ang II–induced hypertrophy and apoptosis [247]. Compared with control mice, in mice deficient in the ASK1 gene, prolonged exposure to Ang II initiates a reduction in cardiomyocyte apoptosis, decreased hypertrophy, attenuated upregulation of hypertrophy-related mRNAs, and diminished pathological changes such as interstitial fibrosis and coronary remodeling [247, 248].

Ca²⁺ overload

Intracellular Ca²⁺ overload is a critical component of the apoptotic signaling triggered by mechanical strain [249]. Elevated mechanical strain leads to a rapid rise in intracellular Ca²⁺ levels, which contributes to promotes cardiomyocyte apoptosis. The use of Ca²⁺ chelators or the blockade of L-type Ca²⁺ channels to decrease intracellular Ca²⁺ levels can mitigate the apoptotic effects caused by mechanical strain, such as the activation of caspase-3 and caspase-9, the generation of ROS, and changes in the mitochondrial membrane potential [30].

Moreover, Ca²⁺ overload can also induce ER stress [250], which serves as a crucial upstream mechanism in multiple forms of programmed cell death, including apoptosis, necroptosis, and pyroptosis. A key mediator in this process is the IP3R, a Ca²⁺ channel located on the endoplasmic reticulum (ER). Upon activation, IP3Rs facilitate the release of Ca²⁺ from the ER into the cytoplasm and mitochondria, leading to mitochondrial Ca²⁺ overload, opening of the mitochondrial permeability transition pore (mPTP), oxidative stress, and subsequent cell death. Persistent IP3R signaling can exacerbate cardiomyocyte dysfunction under pressure overload conditions and may contribute to both apoptotic and necroptotic pathways in PO-HCM.

Genetic regulatory mechanisms

Bcl-2 is a critical regulator of apoptosis, and the Bcl-2/Bax ratio is vital in determining the fate of cardiomyocytes under hypertensive conditions. Research has indicated that both mechanical strain and exposure to Ang II lead to upregulate the proapoptotic protein Bax without significant changes in the levels of the antiapoptotic protein Bcl-2, thereby leading to a decreased Bcl-2/Bax ratio and initiates apoptosis [251, 252]. Furthermore, Ang II can increase caspase-3 activity in both spontaneously hypertensive (SHR) and normotensive (WKY) rats, indicating the involvement of caspase-3 in the apoptotic process of hypertensive cardiomyocytes [252]. Fas, a surface molecule of the TNF and nerve growth factor (NGF) receptor family, engages with its ligand FasL to initiate apoptosis in Fas-positive cells. Under conditions of mechanical strain, the protein expression of Fas increases in cardiomyocytes, contributing to initiating apoptosis [242].

MAPK signaling pathway

Under conditions of overload, the receptors for hypertrophic factors are typically G protein-coupled receptors (GPCRs). In the initial phases of chronic pressure or volume overload, low-level activation of the G protein alpha subunit q type (Gq) protein primarily drives hypertrophy through the MAPK pathway. As overload persists, there is increased secretion of hypertrophic factors, which results in enhanced Gq activation. This heightened Gq signaling activates both the MAPK pathway and apoptotic signaling pathways, eventually initiating cardiomyocyte apoptosis [253].

Mitochondrial pathway

In PO-HCM, mitochondrial damage can lead to the release of cytochrome C into the cytoplasm [254]. Cytochrome C then binds to apoptotic protease-activating factor-1 (Apaf-1), promoting the assembly of the apoptosome [255]. The formation of this complex activates caspase-9, which initiates the intrinsic apoptotic pathway, ultimately resulting in cardiomyocyte apoptosis [232].

Death receptor pathway

In PO-HCM, death receptors located on the surface of cardiomyocytes, such as Fas and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors, can be activated. When these receptors bind to their respective ligands, FasL or TRAIL, they activate caspase-8 or caspase-10. This activation initiates the extrinsic apoptotic pathway, culminating in cardiomyocyte apoptosis.

In addition to Fas and TRAIL receptors, members of the tumor necrosis factor receptor (TNFR) family, particularly TNFR1, also acts as a pivotal effector molecule in cardiomyocyte apoptosis [256]. Upon binding of TNF-α, TNFR1 recruits adaptor proteins such as TRADD (TNF receptor-associated death domain) and FADD (Fas-associated death domain), leading to the formation of a death-inducing signaling complex (DISC) and activation of caspase-8. This pathway contributes significantly to inflammation-driven cardiac apoptosis. In contrast, TNFR2, which lacks a death domain, may regulate cell survival or immune signaling depending on the context. In PO-HCM, chronic inflammatory stimuli and elevated TNF-α levels may shift the TNFR1/TNFR2 balance toward apoptosis and adverse remodeling.

Endoplasmic reticulum stress pathway

In PO-HCM, the ER within cardiomyocytes may undergo stress, resulting in the accumulation of unfolded or misfolded proteins. This ER stress can trigger the activation of caspase-12, leading to the initiation of the apoptotic process in cardiomyocytes [257].

When apoptosis becomes insufficient or dysregulated, cardiomyocytes may shift toward alternative cell death programs—such as necroptosis—especially under sustained pressure overload and reduced caspase activity.

Potential therapeutic strategies

In managing PO-HCM, improving the hemodynamic status of the heart to reduce the cardiac burden can involve the use of medications such as β-blockers or Ca²⁺ channel blockers to modulate the neurohumoral system and inhibit the overactive sympathetic nervous system (Table 3). Additionally, targeting key molecules in cellular signaling pathways with inhibitors to block proapoptotic signals or enhance antiapoptotic signals may be beneficial (Table 3). For patients with known genetic factors, gene therapy could provide a long-term solution by correcting or compensating for genetic mutations that lead to disease. Combining these strategies may more effectively combat cardiomyocyte apoptosis, slow disease progression and improve patients’ quality of life.

Table 3.

Role of small-molecule drugs in the treatment of apoptosis in cardiomyopathy

Compound	Mechanism of action	Effect on apoptotic signaling	Clinical Phase	References
Astragalus polysaccharides	Downregulates the expression of activating transcription factor 6 (ATF6) and protein kinase RNA-like ER kinase (PERK)	Reduces apoptosis	Preclinical	[258]
Clemastine fumarate	TLR4, NF-κB, TNF-α, and Bax expression is downregulated, Bcl-2,p-PI3K, and pAkt expression is upregulate, SOD activity is decreased	Anti-inflammation, anti-oxidative stress, and antiapoptosis	Preclinical	[259]
Curcumin	Bax expression is downregulated, Bcl-2 expression is upregulate, SOD activity is augmented, and MDA is decreased	Inhibition of Apoptosis	Preclinical	[260]
CVB-D	Increases PGC-1α and Nrf1 levels, and enhances mitochondrial biogenesis	Inhibition of apoptosis	Preclinical	[261]
Diprivan	Bax and Caspase-3 expression is downregulated, Bcl-2, p-PI3K, and p-Akt expression is upregulate	Inhibition of apoptosis	Preclinical	[262, 263]
Dihydroquercetin	Bax and Caspase-3 expression is downregulated, Bcl-2, p-PI3K, and p-Akt expression is upregulate, SOD activity is decreased	Inhibition of Apoptosis	Preclinical	[264]
Ferrugino	Upregulates PGC-1α, promotes PGC-1α activation mediated by Sirt1 deacetylation, and enhances mitochondrial biogenesis	Inhibition of apoptosis	Preclinical	[265]
Guhong injection	Inhibit oxidative stress	Inhibition of apoptosis	Preclinical	[266]
Ginsenoside Rc	Inhibit oxidative stress	Inhibition of apoptosis	Preclinical	[267]
Ginsenoside	Bax expression is downregulated, Bcl-2, p-PI3K, and p-Akt expression is upregulate	Inhibition of Apoptosis	Preclinical	[268]
Harpagoside	Promotes Parkin translocation to mitochondria and restores Parkin-mediated mitophagy	Inhibition of Apoptosis	Preclinical	[269]
Honokiol	Bax and Caspase-3 expression is downregulated, Bcl-2, p-PI3K, and p-Akt expression is upregulated	Inhibition of Apoptosis	Preclinical	[270]
Hyperoside	Bax expression is downregulated, Bcl-2, p-PI3K, and p-Akt expression is upregulated	Inhibition of Apoptosis	Preclinical	[271]
Luteolin	Attenuates mitochondrial injury, and promotes mitophagy via activation of Drp1/mTOR/TFEB pathway	Inhibition of Apoptosis	Preclinical	[272]
Liensinine	Reduces Rab7 level and inhibits mitophagy flux Decreases Drp1 phosphorylation and mitochondrial fission	Inhibition of Apoptosis	Preclinical	[73]
LCZ696	Decreases Drp1 and its phosphorylation, and inhibits mitochondrial fission	Inhibition of Apoptosis	Preclinical	[274]
Notoginsenoside R1	Up-regulation of AMPK/ Nrf2 signaling and HO-1 expression	Reduces cardiomyocyte death, apoptosis, and hypertrophy	Preclinical	[2876]
Sinomenine	Inhibit oxidative stress, inflammatory reaction	Inhibition of Apoptosis	Preclinical	[276]
Tanshinone IIA	Bax and Caspase-3 expression is downregulated, Bcl-2, p-PI3K, and p-Akt expression is upregulated	Inhibition of Apoptosis	Preclinical	[277]
Tylenine	Bax expression is downregulated, Bcl-2, p-PI3K, and p-Akt expression is upregulated	Inhibition of Apoptosis	Preclinical	[278]

Researchers have identified multiple mechanisms—hemodynamic overload, neurohumoral dysregulation, intracellular signaling, and genetic alterations—that collectively promote cardiomyocyte apoptosis in PO-HCM. Further research will deepen our understanding of PO-HCM and its pathogenesis, providing theoretical support for the development of effective therapeutic strategies. By inhibiting mitochondrial pathways and death receptor pathways and regulating ER stress pathways while combining both pharmacological and nonpharmacological treatments, it may be possible to reduce the risk of cardiomyocyte apoptosis in PO-HCM, thereby improving patient outcomes and quality of life.

Necroptosis

Necroptosis is a form of programmed cell death that is activated as an alternative pathway when cells cannot undergo normal apoptosis [279]. Although it appears similar to necrosis, necroptosis is regulated by specific mechanisms that rely on RIPK3-mediated phosphorylation of MLKL rather than on caspase activity [280]. The phosphorylation of MLKL promotes its aggregation at the plasma membrane, forming pore-like structures that lead to the release of damage-associated molecular patterns (DAMPs), cellular swelling, and ultimately, cell membrane rupture [281]. A notable feature of necroptosis is the formation of necrosomes, complexes primarily composed of RIPK1 and RIPK3 [282]. When a cell receives a death signal, RIPK1 and RIPK3 aggregate to form higher-order structures, with RIPK3 phosphorylation playing a crucial role in activating downstream effector molecules, including MLKL, leading to membrane disruption and cell death.

Molecular mechanisms of necroptosis in PO-HCM

Recent studies have increasingly focused on the role of necroptosis in PO-HCM [283]. Members of the RIPK family, particularly RIPK1, RIPK3, and MLKL, the principal effector peptide in this process [284]. RIPK3 activates MLKL by phosphorylating threonine 357 and serine 358 residues, transforming MLKL from a monomer to an oligomer [285, 286], which then translocates to the plasma and organelle membranes, binds to phospholipids, disrupts the membrane integrity, and triggers necroptosis [287, 288] (Fig. 6).

Fig. 6.

The molecular mechanisms of necroptosis and pyroptosis in PO-HCM. Abbreviations: AIM2, absent in melanoma 2; CaMKII, calcium/calmodulin-dependent protein kinase II; DAMPs, damage-associated molecular patterns; dsDNA, double-stranded DNA; Drp1, dynamin-related protein 1; ER Stress, endoplasmic reticulum stress; GSDMD, gasdermin D; GSDME, gasdermin E; MLKL, mixed lineage kinase domain-like pseudokinase; mPTP, mitochondrial permeability transition pore; NAD⁺, nicotinamide adenine dinucleotide; NLRP3, NOD-, LRR- and pyrin domain-containing protein 3; PARP-1, poly(ADP-ribose) polymerase 1; PGAM5, phosphoglycerate mutase family member 5; RIPK1/3, receptor interacting serine/threonine protein kinase 1/3; ROS, reactive oxygen species

Investigators have detected increased RIPK3 transcript levels in PO-HCM patients and linked them to poor heart failure outcomes [289, 290]. These findings suggest that the RIPK family plays an important regulatory role in cardiomyocytes during pressure overload. Furthermore, cardiac-specific overexpression of RIPK can exacerbate cardiomyocyte death, post-myocardial infarction remodeling, and heart dysfunction [291]. Studies indicate that upon MLKL translocation to the plasma membrane, it may facilitate the influx of Ca²⁺ or sodium ions, resulting in changes in the intracellular osmotic pressure and cell swelling, ultimately leading to necrosis [287, 292]. These findings collectively highlight the potential role of necroptosis in the progression of cardiovascular diseases.

The closest link between myocardial ischemia caused by PO-HCM and cell death is the mPTP. Hypoxia induces anaerobic metabolism and intracellular acidosis; in response, the Na⁺/H⁺ exchanger pumps H⁺ out of the cell, leading to intracellular Na⁺ accumulation. The Na⁺/Ca²⁺ exchanger subsequently transports the excess Na⁺, leading to elevated intracellular Ca²⁺ levels, inducing Ca²⁺ release from the endoplasmic reticulum/sarcoplasmic reticulum and reperfusion [293]. Each of these activities contributes to the initiation of mPTP opening. Classic myocardial cell necrosis is mediated by RIPK1 and RIPK3, particularly through MLKL [294]. In addition to the classic RIPK1/RIPK3/MLKL pathway, calcium/calmodulin-dependent protein kinase II (CaMKII) can also be activated by RIPK3, subsequently opening the mPTP to induce cell death [295]. Additionally, phosphoglycerate mutase 5 (PGAM5) can also be activated by RIPK3. Activated PGAM5 dephosphorylates dynamin-related protein 1 (Drp1), triggering mitochondrial fission and leading to necroptosis [296]. During the development of pressure overload-induced hypertrophy, RIPK3 can activate downstream MLKL, CaMKII, and PGAM5, inducing necroptosis in cardiomyocytes [297]. MLKL directly mediates changes in membrane permeability that lead to necroptosis, whereas CaMKII and PGAM5/CypD induce mPTP opening, referred to as mPTP necrosis, triggered by mitochondrial Ca²⁺ uniporter (MCU). PGAM5/Drp1 mediates mitochondrial fission.

While apoptosis and pyroptosis are often predominant in the early and inflammatory stages of PO-HCM, necroptosis appears to take on a more dominant role in the advanced or decompensated phases. This is characterized by persistent oxidative stress, mitochondrial dysfunction, and activation of RIPK3-MLKL pathways. Notably, pyroptosis is often associated with early immune cell recruitment and IL-1β/IL-18 release, whereas necroptosis, due to its caspase-independent and pro-inflammatory nature, is more sustained and destructive in late-stage myocardial injury [298]. Understanding this temporal shift provides a critical therapeutic window in which necroptosis inhibition may be particularly beneficial—specifically during the transition from compensated hypertrophy to overt heart failure.

Although necroptosis and pyroptosis are mechanistically distinct, both share inflammatory features and contribute to membrane rupture and DAMPs release. The following section explores how pyroptosis, through inflammasome activation and gasdermin-mediated pore formation, further amplifies cardiac inflammation in PO-HCM.

Potential therapeutic strategies

For patients with PO-HCM, inhibiting the RIPK1/RIPK3/MLKL signaling pathway or the expression of death receptors may help reduce the risk of necroptosis in cardiomyocytes in PO-HCM. This can be achieved through specific inhibitors or antibodies (Table 4). Additionally, protecting mitochondrial function or reducing ROS production may help decrease necroptosis in cardiomyocytes. This can be accomplished via the use of antioxidants or mitochondrial protectants (Table 4). Additionally, a comprehensive approach that combines the inhibition of the necroptosis signaling pathway, mitochondrial protection therapy, and gene therapy may more effectively reduce the risk of necroptosis in PO-HCM cardiomyocytes and improve patient outcomes.

Table 4.

Role of small-molecule drugs in the treatment of necroptosis in cardiomyopathy

Compound	Mechanism of action	Effect on necroptotic signaling	Clinical Phase	References
Amlodipine	Inhibition of CaMKII	Inhibition of necroptosis	Preclinical	[299]
CsA	Inhibition of mPTP	Inhibition of necroptosis	Preclinical/Clinical	[300–305]
Dihydromyricetin	Inhibition of oxidative stress, inflammation, and necroptosis through activation of SIRT3	Inhibition of necroptosis	Preclinical	[306]
GSK'872	Inhibition of RIPK3	Inhibition of necroptosis	Preclinical	[297]
H2S	Inhibition of mPTP	Inhibition of necroptosis	Preclinical	[307]
KN-93	Inhibition of CaMKII	Inhibition of necroptosis	Preclinical	[308]
Melatonin	Inhibition of RIPK3 and CaMKII	Inhibition of necroptosis	Preclinical	[309]
NaHS	Inhibition of RIP3	Inhibition of necroptosis	Preclinical	[310]
Nifedipine	CaMKII	Inhibition of necroptosis	Preclinical	[299]
Necrostatin-1	Amlodipine RIPK1, reduction of TNF-α secretion	Inhibition of necroptosis	Preclinical	[311–313]
Paeoniflorin	Directly binds and degrades TNFR1 and regulates the RIPK1/RIPK3 signaling pathway	Reduces p-MLKL protein levels; Inhibition of necroptosis	Preclinical	[314]
ZYZ-803	Inhibition of RIPK3 and CaMKII	Inhibition of necroptosis	Preclinical	[315]
3-T1AM	Inhibition of RIPK1, RIPK3 and CaMKII	Inhibition of necroptosis	Preclinical	[316]

Necroptosis in cardiomyocytes during PO-HCM is a complex process involving multiple molecular mechanisms and influencing factors. Further research will help deepen the understanding of the pathogenesis of PO-HCM and provide theoretical support for the development of effective therapeutic strategies. The comprehensive application of various methods, including inhibition of the necroptosis signaling pathway, mitochondrial protection therapy, gene therapy, and combination strategies, may help reduce the risk of necroptosis in PO-HCM patients and improve their prognosis.

Pyroptosis

Pyroptosis is a form of programmed cell death mediated by inflammasomes and is characterized by cell membrane swelling and rupture, leading to the release of cellular contents and inflammatory factors that promote inflammation and recruit immune cells [317, 318]. This process is triggered by the specific cleavage of gasdermin D (GSDMD) by inflammatory caspases, such as caspase-1, caspase-4, caspase-5, or caspase-11 [319]. Pyroptosis can be classified into a classical pathway dependent on caspase-1 and a nonclassical pathway dependent on caspase-4/5/11, depending on the stimulus.

Molecular mechanisms of pyroptosis in PO-HCM

Recent evidence suggests that pyroptosis is critically implicated in the occurrence and development of PO-HCM [320]. Under pressure overload, the pyroptosis process in cardiomyocytes is markedly enhanced, leading to cell death and dysfunction [321, 322] (Fig. 6).

In PO-HCM, cardiomyocyte pyroptosis occurs primarily via the classical caspase-1-dependent pathway. In this pathway, various inflammasomes, including, NLR family pyrin domain containing 3 (NLRP3) and absent in melanoma 2 (AIM2), are activated by multiple factors, recruiting procaspase-1 to form an inflammasome complex. This complex promotes the oligomerization of procaspase-1, ultimately cleaving it into active caspase-1, which consists of the p20 and p10 subunits. Active caspase-1 converts pro-IL-1β and pro-IL-18 into their mature forms [323] and cleaves GSDMD, forming pores in the plasma membrane that release inflammatory cytokines such as IL-1β and IL-18, triggering an inflammatory response [324–327].

During the development of hypertrophy due to pressure overload, chronic hypoxic-ischemic injury and cellular debris from cardiomyocyte death act as DAMPs, activating inflammasomes and leading to an inflammatory response [328]. Factors such as mitochondrial damage, elevated ROS levels, and disrupted ionic balance contribute to tissue damage and sterile inflammation [329, 330], resulting in the accumulation of neutrophils and macrophages. These inflammatory cells release cytokines, chemokines, and proteases, further promoting inflammation, which enhances myocardial hypertrophy and remodeling. Research has indicated that, in TAC-induced hypertrophic mouse models, the levels of caspase-1 and NLRP3 are significantly elevated, contributing to the production of inflammatory mediators and fibrotic factors and resulting in myocardial fibrosis, hypertrophy, and impaired cardiac function [331, 332]. Additionally, IL-18 gene knockout mice exhibit reduced expression of cardiac hypertrophy-related genes [333], whereas elevated levels of IL-18 are observed in aortic constriction rabbit models during pressure overload [334]. Studies have also shown that in hypertrophied cardiomyocytes, the expression levels of caspase-1 and IL-1β are significantly upregulated and that inhibiting the NLRP3 inflammasome and caspase-1 can alleviate cardiac remodeling and heart failure caused by pressure overload [335, 336], as well as Ang II induced hypertrophy [337, 338].

Further studies [339] revealed that, in pressure overload models, NLRP3 knockout mice presented reduced cardiomyocyte pyroptosis and improved cardiac function. In vitro experiments with neonatal mouse ventricular myocytes treated with the NLRP3 inhibitor MCC950 revealed reduced pyroptosis and hypertrophy induced by Ang II. When caspase-1 or GSDMD is overexpressed in NLRP3 knockout mice and MCC950-treated neonatal mouse ventricular myocytes under TAC or Ang II stimulation, either direct overexpression of GSDMD or indirect overexpression of caspase-1 promotes pyroptosis, counteracting the protective effect of NLRP3 knockout. Mechanistically, pressure overload activates transforming growth factor-beta activated kinase 1 (TAK1), and the absence of NLRP3 further enhances this activation. Protein interaction network analysis and coimmunoprecipitation experiments confirmed the interaction between NLRP3 and TAK1. Finally, cardiac-specific TAK1 knockout in wild-type and NLRP3 knockout mice exacerbated cardiac remodeling and pyroptosis, further demonstrating the crucial role of the NLRP3–TAK1 signaling pathway in maintaining cardiomyocyte pyroptosis and hypertrophy homeostasis.

Pyroptosis plays a pivotal role in the pathogenesis of inflammatory cardiomyopathy through its potent pro-inflammatory effects. Activation of the NLRP3 inflammasome in cardiomyocytes and resident macrophages leads to caspase-1 dependent cleavage of GSDMD, promoting membrane pore formation and the release of pro-inflammatory cytokines such as IL-1β and IL-18 [320]. These cytokines recruit immune cells, amplify inflammatory signaling, and promote myocardial fibrosis and remodeling. In pressure-overload conditions, sustained inflammasome activation and pyroptotic cell death contribute to a chronic inflammatory milieu, resembling key features of inflammatory cardiomyopathy. This cross-talk highlights the potential of targeting inflammasome components or downstream effectors to attenuate both pyroptosis and inflammatory progression in PO-HCM.

Potential therapeutic strategies

For patients with PO-HCM, certain medications, such as antioxidants and anti-inflammatory drugs, may have potential therapeutic effects. These drugs may reduce the risk of myocardial cell pyroptosis by increasing the antioxidant capacity of myocardial cells and inhibiting the activation of inflammasomes (Table 5). Additionally, gene therapy targeting specific genetic mutations associated with PO-HCM may help restore normal myocardial cell function and lower the risk of pyroptosis. Additionally, the integration of various approaches, such as inhibiting inflammasome activation, antioxidant therapy, and gene therapy, could effectively reduce the risk of pyroptosis in the myocardial cells of PO-HCM patients and improve their prognosis.

Table 5.

Role of small-molecule drugs in the treatment of pyroptosis in cardiomyopathy

Compound	Mechanism of action	Effect on pyroptotic signaling	Clinical Phase	References
Colchicine	Inhibition of NLRP3 inflammatory vesicle, caspase-1, IL-1β, and MMP2 and MMP9 expression	Inhibition of pyroptosis	Preclinical	[340, 341]
Cathepsin B	Enhanced the activation of the NLRP3/Caspase-1 inflammasome pathway	Activate of pyroptosis	Preclinical	[342]
Flavonoid	Reduces oxidative stress, inhibits NLRP3 inflammatory vesicle activation, reduces inflammation and cell death	Inhibition of pyroptosis	Preclinical	[343]
Fufang Zhenzhu Tiaozhi	Decreased lipid toxicity, alleviated mitochondrial dysfunction and increase of ROS, thereby inhibiting NLRP3 inflammasome activation	Inhibition of pyroptosis	Preclinical	[344]
Liraglutide	Inhibition of NLRP3 inflammatory vesicle activation, reduction of inflammatory factor production, antioxidant effects	Inhibition of pyroptosis	Preclinical	[345]
Low-dose tretinoin	Blockade of NLRP3 inflammatory vesicle complex assembly and inhibition of NLRP3-TGF-β1-Smad pathway activation	Inhibition of pyroptosis	Preclinical	[331, 346]
Melatonin	Inhibition of NLRP3, ASC, caspase-1, GSDMD and IL-18/1β, MEG3/miR-223/NLRP3	Inhibition of pyroptosis	Preclinical	[347]
Metformin	Inhibited mitochondrial complex I and activated AMPK and autophagy, subsequently downregulated the NLRP3/Caspase-1 pathway via mTOR	Inhibition of pyroptosis	Preclinical	[155]
Puerarin	Inhibits the activation of NLRP3 inflammatory vesicles, reduces the release of inflammatory factors (e.g., IL-1β and IL-18), and inhibits signaling pathways such as NF-κB	Inhibition of pyroptosis	Preclinical	[348, 349]
Pigment epithelium derived factor	Inhibition of mitochondrial division and inactivation of NLRP3 inflammatory vesicles	Inhibition of pyroptosis	Preclinical	[350]
PQQ	Inhibited ROS production and NF-κB activation, thereby reducing the activation of the NLRP3 inflammasome	Inhibition of pyroptosis	Preclinical	[351]
Palmitic acid	Induced to abnormal accumulation of mtROS and activation of cGAS- STING pathway, and leaded to NLRP3 inflammasome-dependent pyroptosis	Activate of pyroptosis	Preclinical	[352]
Skimmin	Enhanced mitochondrial autophagy and decreased mtROS, thereby inhibiting NLRP3 inflammasome activation	Inhibition of pyroptosis	Preclinical	[353]
NLRP3/AIM2-IN-3	Inhibition of NLRP3 and AIM2 inflammasomes	Inhibition of pyroptosis	Preclinical	[354]
MCC950	Inhibition of NLRP3	Inhibition of pyroptosis	Preclinical	[355]
CY-09	Inhibition of NLRP3 inflammatory vesicle	Inhibition of pyroptosis	Preclinical	[356]

The pyroptosis of myocardial cells in PO-HCM is a complex process involving multiple molecular mechanisms and influencing factors. Further research will contribute to a deeper understanding of the pathogenesis of PO-HCM and provide theoretical support for the development of effective therapeutic strategies. The comprehensive application of strategies, including the inhibition of inflammasome activation, antioxidant therapy, gene therapy, and combination treatments, may help reduce the risk of pyroptosis in the myocardial cells of PO-HCM patients and improve their outcomes.

Conclusion

In PO-HCM, programmed cell death of cardiomyocytes encompasses various forms, including autophagy, ferroptosis, apoptosis, necroptosis, and pyroptosis. These forms of death do not exist in isolation, but are closely related and interact with each other (Fig. 7). Recently, the concept of PANoptosis has emerged as a unified form of programmed cell death that encompasses and integrates the mechanisms of pyroptosis, apoptosis, and necroptosis [357]. Unlike isolated forms of cell death, PANoptosis is executed through a distinct molecular complex known as the PANoptosome, which involves key regulators such as Z-DNA binding protein 1 (ZBP1), receptor-interacting protein kinase 3 (RIPK3), caspase-8, and GSDMD. Although PANoptosis has not been specifically characterized in PO-HCM, the coexistence of inflammatory stress, mitochondrial dysfunction, and oxidative injury in this disease context suggests its potential involvement. Recognizing PANoptosis as a potential driver of cardiomyocyte death could help unify diverse signaling events and support the development of multi-targeted therapeutic approaches.

Fig. 7.

Links between various programmed cell death in PO-HCM. Abbreviations: ACSL4, acyl-CoA synthetase long chain family member 4; ER stress, endoplasmic reticulum stress; GSDMD, gasdermin D; GSDME, gasdermin E; LC3, microtubule-associated protein 1 light chain 3; MLKL, mixed lineage kinase domain-like pseudokinase; mTORC1, mechanistic target of rapamycin complex 1; PARP1, poly (ADP-ribose) polymerase 1; PUFA-PL, polyunsaturated fatty acid-containing phospholipids; PUMA, p53 upregulated modulator of apoptosis; ROS, reactive oxygen species; UPR, unfolded protein response

In conclusion, programmed cell death has a decisive influence on the development of PO-HCM. A comprehensive investigation into the mechanisms of cardiomyocyte death will facilitate a thorough understanding of the pathological processes underlying PO-HCM, which is essential for early diagnosis and effective treatment. These studies not only open new avenues for the prevention and treatment of PO-HCM but also have the potential to advance research on other cardiovascular diseases. By identifying key biomarkers and molecular targets, it becomes possible to develop more precise treatment regimens that aim to reduce side effects and enhance therapeutic efficacy. Furthermore, these findings pave the way for the development of innovative therapies, such as gene therapy and cell therapy. Therefore, the in-depth study of programmed cell death in PO-HCM not only enriches the theoretical knowledge in the field of life sciences but also significantly contributes to the improvement of human health.

Limitations

Although this review comprehensively summarizes current findings on programmed cell death mechanisms in PO-HCM, several limitations remain. First, most of the available data derive from preclinical animal models or in vitro studies, which may not fully replicate the complexity of human PO-HCM. Second, the interaction and crosstalk among different forms of programmed cell death—such as apoptosis, necroptosis, pyroptosis, autophagy, and ferroptosis—remain incompletely understood, especially under dynamic pressure-overload conditions. Third, limited clinical evidence is currently available regarding the efficacy and safety of therapeutically targeting these cell death pathways in PO-HCM patients. Fourth, while this review focuses primarily on cardiomyocytes, other cardiac cell types—including fibroblasts, endothelial cells, and immune cells—may also contribute to pathological remodeling and influence cardiomyocyte fate through intercellular signaling, which warrants further investigation. Lastly, the literature included in this review is subject to heterogeneity in experimental models, definitions, and outcome measures, which may limit the comparability of findings and introduce interpretative bias. These gaps underscore the need for future studies using standardized criteria, clinically relevant models, and longitudinal designs to validate the translational potential of targeting programmed cell death in PO-HCM.

Author contributions

F.X., H.L. L., and J.R.W. helped search the literature and prepare the manuscript; H.M.W., Y.Q. C., and J.W. W. prepared figures; H.C., G.L., Z.Y. X., Y.B.X. and S. W. helped with the article modification. All authors read and approved the final manuscript.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of interest

All authors declare that they have no competing interests.

Ethical approval

Not applicable.

Consent for publication

All authors consent this manuscript for publication.