Myocardial infarction is most commonly caused by rupture or erosion of a coronary atherosclerotic plaque, followed by platelet activation, thrombus formation, and acute coronary occlusion. Because cardiomyocytes rely heavily on continuous oxygen delivery and mitochondrial oxidative phosphorylation, interruption of coronary blood flow rapidly induces ATP depletion, ionic imbalance, calcium overload, mitochondrial injury, and cell death. Early reperfusion, antiplatelet therapy, lipid-lowering treatment, and modern heart failure therapy have substantially improved survival [1] [2]. Nevertheless, many patients still develop adverse ventricular remodeling.

Reperfusion is essential for salvaging ischemic myocardium, but it may also trigger oxidative stress, mitochondrial permeability transition, endothelial injury, inflammatory activation, and microvascular dysfunction, collectively contributing to ischemia-reperfusion injury [3] [4]. Because adult mammalian cardiomyocytes have limited regenerative capacity, necrotic myocardium is largely replaced by fibrotic scar tissue. A stable scar prevents ventricular rupture, whereas excessive or persistent fibrosis increases ventricular stiffness, reduces compliance, and promotes heart failure [5]-[7].

Post-infarction repair is therefore a multicellular process involving endothelial cells, immune cells, fibroblasts, vascular smooth muscle cells, and surviving cardiomyocytes. A shared feature of these cells is reliance on cytoskeletal reorganization and actomyosin-mediated force generation. MRCK is positioned within this biological context. However, direct MI-specific evidence remains scarce. Thus, this article should be read as a prospective conceptual framework: MRCK may be important in MI not because it has already been proven to determine infarct formation, but because its known functions match several underexplored mechanical aspects of post-infarction repair.

MRCK belongs to the myotonic dystrophy kinase-related serine/threonine kinase family. The major mammalian isoforms are MRCKα, MRCKβ, and MRCKγ, encoded by CDC42BPA, CDC42BPB, and CDC42BPG, respectively [8]-[11]. MRCKα and MRCKβ are the best characterized and participate in actin organization, cell polarity, migration, cell junction regulation, and tissue remodeling.

MRCK proteins contain an N-terminal kinase domain, a central coiled-coil region, and C-terminal regulatory domains involved in membrane localization, small GTPase binding, and autoinhibition [12]. Their best-known upstream regulator is Cdc42, a Rho-family small GTPase that controls cell polarity, protrusion formation, directional migration, and junctional organization [8] [10] [11]. Through this structure, MRCK converts spatial Cdc42-related signals into localized actomyosin contractility.

A major downstream function of MRCK is regulation of myosin light-chain phosphorylation and non-muscle myosin II activity [9] [13]. This enables MRCK to influence cell shape change, leading-edge dynamics, matrix traction, junctional tension, and cell migration. These are precisely the types of cellular behaviors required during tissue repair after MI.

The absence of extensive MRCK research in MI does not necessarily mean that MRCK is unimportant. Several reasons may explain this gap.

First, MI research has traditionally emphasized coronary occlusion, cardiomyocyte death, reperfusion injury, inflammation, fibrosis, and neurohormonal activation. Local cytoskeletal mechanics, junctional tension, and cell migration machinery have received comparatively less attention, especially in translational cardiovascular studies.

Second, ROCK has dominated the field of actomyosin-related cardiovascular research. RhoA-ROCK signaling is closely linked to vascular tone, vasospasm, hypertension, smooth muscle contraction, and cardiac hypertrophy [13]-[15]. Because ROCK has available inhibitors and obvious hemodynamic relevance, many questions involving myosin light-chain phosphorylation have been interpreted mainly through the ROCK pathway. MRCK, which overlaps with ROCK at the level of actomyosin regulation, may therefore have been considered redundant.

Third, selective MRCK tools have historically been limited. Early pharmacological inhibitors lacked sufficient selectivity or were developed mainly in cancer and cell migration research. In addition, MRCK isoforms may show functional compensation and cell type-specific behavior, making whole-body inhibition or nonspecific knockout models difficult to interpret.

Finally, MRCK may have bidirectional roles after MI. It may stabilize endothelial junctions in one context but promote leakage in another; it may support early scar formation but worsen late fibrosis. Such stage- and cell-dependent effects make MRCK harder to classify as simply protective or harmful. This complexity may have delayed its systematic evaluation in MI.

MRCK and ROCK both regulate myosin light-chain phosphorylation and actomyosin contraction, but they are not interchangeable. ROCK is mainly activated by RhoA and is commonly associated with global cellular tension, central stress fiber formation, vascular smooth muscle contraction, vasospasm, hypertension, and cardiac hypertrophy [13]-[15]. In contrast, MRCK is primarily linked to Cdc42-related signaling and more often regulates local contraction, cortical tension, cell polarity, leading-edge dynamics, and junctional remodeling [8]-[11].

This distinction is particularly relevant to MI. ROCK may better explain changes in vascular tone, coronary spasm, and systemic contractile load. MRCK may be more relevant to local cellular behaviors: endothelial junction repair or disruption, leukocyte migration, fibroblast traction, collagen compaction, and scar architecture. Thus, MRCK should not be viewed merely as a weaker or redundant ROCK-like kinase. It may regulate different subcellular compartments, different cell types, and different stages of post-infarction repair.

From a therapeutic perspective, ROCK inhibition may influence vascular tone and global cytoskeletal tension, whereas MRCK modulation may affect localized cellular mechanics. Whether these pathways compensate, cooperate, or diverge after MI remains unknown and should be tested directly in comparative experimental models.

As a Perspective, this article should generate experimentally testable hypotheses rather than provide definitive conclusions.

Hypothesis 1: Endothelial MRCKβ regulates microvascular barrier integrity during early reperfusion.

Junction-localized MRCKβ may protect endothelial integrity, whereas mislocalized or excessive activation may promote leakage and no-reflow. This can be tested using endothelial-specific MRCKβ knockout mice, ischemia-reperfusion models, Evans blue or fluorescent albumin leakage assays, coronary perfusion imaging, VE-cadherin staining, and spatial analysis of phosphorylated myosin light chain [18]-[20] [31].

Hypothesis 2: Fibroblast MRCKα/β has stage-dependent effects on scar formation.

Early MRCK activation may promote scar stabilization, whereas late persistent activation may increase collagen compaction and ventricular stiffness. This can be examined using fibroblast-specific, time-inducible MRCKα/β knockout models, collagen gel contraction assays, traction force microscopy, Picrosirius red staining, cardiac MRI, pressure-volume loop analysis, and rupture-risk assessment [25]-[27] [31].

Hypothesis 3: Myeloid MRCK regulates inflammatory cell trafficking after MI.

MRCK may influence neutrophil and monocyte infiltration, macrophage positioning, and inflammation resolution. Myeloid-specific MRCK knockout, bone marrow chimera experiments, flow cytometry, single-cell RNA sequencing, and intravital imaging could clarify these effects [21]-[23] [31].

Hypothesis 4: MRCK and ROCK have nonredundant functions after MI.

MRCK may regulate localized cell migration and junctional mechanics, whereas ROCK may regulate global contractility and vascular tone. Comparative studies using MRCK inhibitors, ROCK inhibitors, dual inhibition, and genetic models should assess vascular leakage, inflammatory infiltration, fibroblast traction, scar architecture, ventricular stiffness, and ejection function [9] [13]-[15] [31].

Hypothesis 5: Cardiomyocyte MRCK contributes to border-zone mechanoadaptation.

Cardiomyocyte-specific MRCK deletion, cyclic stretch models, phosphoproteomics, super-resolution cytoskeletal imaging, and strain analysis may determine whether MRCK affects non-sarcomeric cytoskeletal remodeling after MI [29]-[31].

These studies should follow a standardized experimental MI model design and should avoid relying solely on systemic pharmacological inhibition, because MRCK function is likely isoform-specific, cell-specific, stage-specific, and spatially localized [31].

Adverse ventricular remodeling after MI remains a major determinant of long-term heart failure, characterized by ventricular dilation, wall thinning, extracellular matrix remodeling, reduced compliance, and progressive contractile dysfunction [32] [33]. Therefore, any translational strategy targeting MRCK should be evaluated not only by acute infarct size or short-term ejection fraction, but also by scar architecture, ventricular stiffness, microvascular integrity, inflammatory resolution, and long-term remodeling outcomes.

Several MRCK inhibitors, including BDP5290, BDP9066, BDP8900, and DJ4, have been developed mainly as research tools in cancer migration and cytoskeletal studies [34] [35]. They may help interrogate MRCK function in cardiovascular models, but they are not established MI therapies.

Potential applications could include limiting excessive fibroblast contraction, reducing chronic scar stiffening, modulating endothelial leakage, controlling inflammatory cell migration, or affecting vascular remodeling. However, these possibilities remain speculative. MRCK inhibition could also impair endothelial junction stabilization, delay inflammatory clearance, weaken early scar formation, or disturb normal wound healing [27]. Therefore, the translational question is not simply whether MRCK should be inhibited, but when, where, in which cell type, and for how long. Local delivery, short-course treatment, infarct-border-zone targeting, nanoparticles, hydrogels, or device-based delivery may be more realistic than chronic systemic inhibition.

This article is a perspective and a hypothesis-generating review. Current evidence is insufficient to define MRCK as an established therapeutic target in MI. Nevertheless, MRCK regulates actomyosin contraction, cell polarity, migration, and junctional remodeling―processes that are central to post-infarction repair. MRCK may influence endothelial barrier integrity, inflammatory cell recruitment, fibroblast-mediated scar mechanics, vascular remodeling, cardiomyocyte mechanoadaptation, and ultimately ventricular remodeling.

The main message is not that MRCK has already been proven to drive MI pathology, but that it represents an underexplored mechanobiological pathway that deserves systematic investigation. Future studies should define their isoform-specific, cell-specific, stage-specific, and spatially localized functions. If these mechanisms are clarified, MRCK may open a new direction for modulating post-infarction repair through control of cellular mechanics.

This work was sponsored by Tianjin Health Research Project (TJWJ2022XK026), National Natural Science Foundation of China (82370420), and Tianjin Key Medical Discipline Construction Project (TJYXZDXK-3-010B).

The authors declare no conflicts of interest regarding the publication of this paper.