The Underexplored Mechanobiology of Lamin A Biogenesis and Homeostasis

ABSTRACT

Lamin A is a major contributor to nuclear mechanics and an important mediator of mechanotransduction. While its role in regulating nuclear architecture is well established, considerably less attention has been given to how mechanical cues regulate lamin A itself. Here, we review current evidence demonstrating that lamin A homeostasis is dynamically controlled by mechanical stimulation through transcriptional, translational, and post‐translational mechanisms regulating protein abundance, stability, and turnover. We further discuss emerging evidence suggesting that prelamin A maturation, a highly conserved multistep processing pathway, may represent a previously unrecognized mechanosensitive regulatory node. Recent studies challenge the canonical model of prelamin A processing and raise the possibility of alternative maturation pathways with important implications for lamin A homeostasis. We highlight current evidence, unresolved questions, and future directions, proposing that mechanical regulation of lamin A biogenesis represents an underexplored dimension of lamin mechanobiology with broad implications for development, aging, laminopathies, and mechanically driven diseases.

We highlight current evidence, unresolved questions, and future directions, proposing that mechanical regulation of lamin A biogenesis represents an underexplored dimension of lamin mechanobiology with broad implications for development, aging, laminopathies, and mechanically driven diseases.

1. Introduction

The nuclear lamina is one of the key mechanosensitive structures that integrate mechanical signals within the nucleus. Through its connection to the LINC (linker of nucleoskeleton and cytoskeleton) complex, forces are transmitted from the cytoskeleton to the nuclear envelope. Nesprins at the outer nuclear membrane and SUN domain proteins at the inner nuclear membrane relay these forces to the lamina, enabling structural adaptation of the nucleus and regulation of gene expression (Padmakumar et al. 2005; Crisp et al. 2006; Solovei et al. 2013; Maraldi et al. 2011). Different lamin isoforms—lamins A, B, and C assemble into this lamina meshwork lining the nuclear envelope that supports the nuclear architecture and regulates key processes essential for cell survival, such as proliferation, senescence, and differentiation (Röber et al. 1989).

Mutations in nuclear lamina proteins give rise to a spectrum of human diseases, collectively known as laminopathies, ranging from muscular dystrophies to premature aging, underscoring the critical structural and functional roles of this nuclear protein network (for review go to (Schreiber and Kennedy 2013)). Moreover, through their physical interaction with chromatin, lamins are involved in chromatin organization (Solovei et al. 2013), gene regulation and genome stability and act as regulatory hubs for transcription factors and signaling pathways (Maraldi et al. 2011; Ho et al. 2013; Buxboim et al. 2014; Tao et al. 2025).

Mechanically speaking, the nucleus has been modeled as a viscoelastic material where chromatin and lamin A are known to be the key nuclear mechanical components (Wintner et al. 2020). While chromatin dominates the mechanical response at small deformations, lamin A/C becomes increasingly load‐bearing under large strains, where it mediates nuclear strain stiffening and protects against structural failure (Stephens et al. 2017). Lamin A is not simply a rigid structural scaffold, but it can also behave as a complex viscoelastic material whose mechanical response depends strongly on strain and network organization. Banerjee et al. report a nonlinear strain‐softening response of lamin A network with increasing shear deformation (Banerjee et al. 2013). The role of the nuclear lamina—particularly lamin A/C—in nuclear mechanics and mechanotransduction is well established (Buxboim et al. 2023; Osmanagic‐Myers et al. 2015). Yet, despite extensive evidence that lamin A/C abundance adapts to tissue stiffness, extracellular matrix mechanics, confinement, and other mechanical perturbations, the mechanisms linking these physical cues to lamin A/C biogenesis and homeostasis remain poorly understood. Here, we shift the perspective from how lamin A/C regulates nuclear mechanics to how mechanical cues regulate lamin A/C itself, with particular emphasis on the emerging and underexplored role of prelamin A processing.

2. Birth of Lamin A: From Gene Expression to Post‐Translational Regulation

A‐type lamins arise from the transcription of LMNA gene coding for the major isoforms, lamin A and lamin C, resulting from alternative splicing. Lamins B1 and B2 are encoded and expressed independently (LMNB1 & LMNB2 genes). Lamin C is directly mature upon translation whereas lamin A matures following complex post‐translational modifications of prelamin A protein (Gruenbaum and Foisner 2015) (Figure 1). The currently accepted prelamin A processing pathway begins with farnesyltransferase that first transfers a farnesyl residue to the cysteine at the CAAX terminus, a step essential for prelamin localization to the nuclear periphery (Gruenbaum and Foisner 2015; Sinensky et al. 1994). Then, the last three AAX amino acids are cleaved by RCE1 or ZMPSTE24 metallopeptidase, followed by the addition of a methyl group to the C‐terminal farnesylated phospho residue by an isoprenylcysteine carboxymethyltransferase (ICMT) (Ibrahim et al. 2015). Mature lamin A—but not lamin B that also contains CAAX—is obtained by an additional proteolytic cleavage of 15 amino acids upstream of the farnesylated cysteine by ZMPSTE24 (Barrowman et al. 2012). This processing step removes the C‐terminal farnesyl group and leaves a tyrosine residue at the carboxyl end of mature lamin A (Figure 1). Based on the literature (Nie et al. 2020; Quickley et al. 2013; Barrowman et al. 2008; Yao et al. 2020; Chen et al. 2021), an alternative possibility could also come from the direct cleavage by ZMPSTE24 generating mature lamin A before processing the CSIM motif (direct cleavage pathway, see Box 1 for noncanonical model of prelamin A processing). Although its physiological relevance remains to be established, this alternative pathway would considerably reshape our current understanding of the molecular sequence of prelamin A maturation and the respective contributions of RCE1, ICMT, and ZMPSTE24. An important aspect of this alternative model is that the relative contribution of the different processing routes is likely to depend on where and when the processing enzymes encounter prelamin A within the cell.

FIGURE 1.

Lamin A biogenesis, processing and mechanical regulation steps. The upper panel illustrates the organization of the nuclear envelope and its connections to the major cytoskeletal networks through the LINC complex. The different lamin isoforms are shown on the right. Following LMNA transcription and translation, prelamin A undergoes four sequential post‐translational processing steps in the canonical maturation pathway. (1) Farnesylation of the C‐terminal cysteine by farnesyltransferase (FTase), followed by (2) proteolytic removal of the three terminal amino acids (SIM) by RCE1 or ZMPSTE24, exposing the farnesylated cysteine for (3) ICMT‐mediated carboxymethylation. A final proteolytic cleavage by ZMPSTE24 removes the last 15 amino acids, including the farnesylated cysteine, generating mature lamin A (4). Enzymes involved in each processing step are highlighted in green. Established and emerging mechanisms through which mechanical cues regulate lamin A biogenesis, maturation, and homeostasis are summarized in purple. See Box 1 for alternative models of prelamin A maturation.

BOX 1 | More than one route to mature lamin A?

The canonical model of prelamin A maturation was largely extrapolated from the processing of CAAX proteins, particularly the yeast mating pheromone A‐factor. However, the CSIM sequence of prelamin A represents a noncanonical CAAX motif because serine (S) is not an aliphatic residue. Maturation of the yeast mating pheromone A‐factor involves canonical CAAX processing together with additional proteolytic cleavages, including one mediated by STE24, the yeast homolog of ZMPSTE24. This model was subsequently supported by genetic, biochemical, and pharmacological studies and became the accepted pathway for prelamin A maturation.

Recent studies from Carpenter group have revisited this model using complementary genetic, structural, biochemical, and yeast approaches (Nie et al. 2020). The first indication that prelamin A might not follow the canonical processing pathway came from genetic studies. RCE1 is considered the canonical enzyme responsible for AAX cleavage of CAAX proteins. However, prelamin A does not accumulate in RCE1‐deficient cells (Barrowman et al. 2012), indicating that lamin A maturation can proceed in the absence of RCE1. Likewise, ste24 is sufficient to support maturation of the yeast mating pheromone A‐factor in *rce1Δ* yeast (Nie et al. 2020), suggesting that ZMPSTE24 may also contribute to the early proteolytic processing of prelamin A. These observations prompted a closer examination of how ZMPSTE24 recognizes the prelamin A C‐terminus. Carpenter group determined the crystal structure of ZMPSTE24 in complex with the C‐terminal tetrapeptide (CSIM) of prelamin A (Quickley et al. 2013). Unexpectedly, the orientation of the tetrapeptide within the catalytic chamber favored cleavage after the IM dipeptide (CS↓IM), rather than the canonical SIM tripeptide (C↓SIM). Consistent with this prediction, mass spectrometry analysis of prelamin A C‐terminal peptides incubated with ZMPSTE24 identified the IM dipeptide as the predominant cleavage product, whereas only trace amounts of the expected SIM cleavage product were detected. The authors proposed that longer prelamin A substrates may adopt a different conformation within the catalytic chamber, potentially influencing cleavage specificity.

The implications of these findings were further explored using mass spectrometry‐based kinetic analyses of ZMPSTE24 cleavage products (Nie et al. 2020). In vitro, in the absence of RCE1, the earliest products generated from farnesylated prelamin A C‐terminal peptides corresponded to cleavage at the upstream ZMPSTE24 site (step 4 in Figure 1), indicating that ZMPSTE24 is intrinsically capable of generating mature lamin A before processing the CSIM motif (direct cleavage pathway). This sequence therefore differs fundamentally from the canonical model, in which CAAX processing and ICMT‐mediated carboxymethylation precede the final ZMPSTE24 cleavage. If direct cleavage also occurs in vivo, carboxymethylation would no longer be an obligatory prerequisite for lamin A maturation, raising the possibility that ICMT‐dependent methylation may serve primarily a regulatory rather than an essential processing function. Given the reported role of ICMT‐mediated carboxymethylation in regulating the AKT signaling pathway (Chen et al. 2021; Yao et al. 2020), bypassing this modification could have functional consequences extending beyond lamin A maturation itself. Dipeptide cleavage products appeared only at later time points, suggesting that CAAX processing by ZMPSTE24 follows, rather than precedes, the upstream cleavage. Whether these two processing pathways coexist in vivo remains unknown. If they do, a key question is how cells regulate the choice between direct ZMPSTE24‐mediated cleavage and the canonical RCE1‐dependent maturation pathway. Determining whether cellular context—including mechanical cues—regulates the relative contribution of these pathways represents an important avenue for future research.

Interestingly, the processing enzymes are found in different cell compartments and are not only located at the nuclear periphery (Barrowman et al. 2008). Farnesyltransferases are found in the cytosol or nucleoplasm and ZMPSTE24, RCE1, and ICMT for long were associated to endoplasmic reticulum (ER) membrane proteins, with their active sites facing the cytosol (Dai et al. 1998; Schmidt et al. 1998). More recently, a detailed investigation of the cellular site of prelamin A processing by Barrowman et al. revealed that ZMPSTE24 and ICMT localize to both the inner nuclear membrane and the endoplasmic reticulum, suggesting that the nucleus is the primary physiological site of prelamin A CAAX processing (Barrowman et al. 2008).

These findings, combined with the recognition of the nuclear envelope as a critical mechanosensitive compartment, have highlighted its potential contribution to mechanotransduction through the regulation of prelamin A post‐translational maturation. This possibility is particularly intriguing because lamin A is a highly stable structural protein produced through a complex multistep biogenesis pathway and maintained by tightly regulated turnover mechanisms. Nevertheless, lamin A/C abundance remains highly responsive to mechanical cues across a wide range of biological systems (Table 1), raising the question of how physical signals are translated into changes in lamin levels. In this review, we first summarize the evidence supporting mechanical regulation of lamin A/C across physiological and pathological contexts. We then discuss the mechanisms that may underlie these responses, including LMNA transcriptional regulation, post‐translational pathways controlling lamin A stability and degradation, and emerging evidence for the mechanical regulation of prelamin A maturation.

TABLE 1.

Major mechanical stimulations, their physiological relevance, and impact on lamin A/C abundance.

Mechanical stimulation	Physiological relevance	Cell type	Consequences on lamin A	Citations
Substrate stiffness	Lineage differentiation	Embryonic stem cells	Lamin A protein quantity scaling with tissue stiffness	(Swift et al. 2013)
			Lamin A/C increases with matrix stiffness	(Roy et al. 2025)
	Cancer	Mesenchymal stem cells MSCs	Matrix elasticity regulates lamin A/C phosphorylation and turn over	(Buxboim et al. 2014)
	Fibrosis	Embryonic hearts iPSc into cardiomyocytes	Myosin II inhibition or ECM stiffness decrease causes rapid lamin A decrease in heart	(Cho et al. 2019)
	Pathological dermal scars	Keloid fibroblasts	Reduction in lamin A/C and redistribution on stiff matrix	(Fu et al. 2024)
	Pulmonary fibrosis	Alveolar epithelial pluripotent stem cells	Under high matrix stiffness, decrease in lamin A/C protein in vitro and tissues of mouse models	(Ba et al. 2025)
	Asthma and chronic obstructive pulmonary disease	Airway smooth muscle	Positive correlation between stiffness and lamin A	(Tan et al. 2024)
Cyclic stretch	Hypertension	Vascular smooth muscle cells	Increased cyclic stretch to 15% decreased the expression of lamin A/C	(Bao et al. 2020; Qi et al. 2016)
		Fibroblasts	15% at 0.5 Hz for 60 min, re‐localization of lamin B1 and lamin A/C with actin cables	(Hoffman et al. 2020)
	Epidermis deformation	Epithelial pluripotent stem cells (EPSc), SCC9 HT1080	40% stretch has no effect on lamin A/C expression	(Nava et al. 2020)
	Osteoarthritis	Chondrocytes	ZMPSTE 24 expression is reduced after 24 h cyclic stretch 20%/5%	(Kong et al. 2023)
Hydrostatic pressure	Inflammation	Macrophages	Compressive force induces transient downregulation of lamin A/C	(Wang et al. 2025)
Osmotic compression	Development	Epithelial cells Drosophila	Apico‐basal compression induces an increase in lamin C	(Lyer et al. 2021)
	Osteoarthritis	Chondrocytes	Decrease in ZMPSTE 24 and lamin A level overloaded chondrocytes	(Kong et al. 2023)
		3T3 fibroblasts	Hyperosmotic compression, nuclear stiffness increases as a function of lamin A/C.	(L. K. Srivastava et al. 2021)
Mechanical compression, confined migration	Cancer	Epithelial MCF7 MCF10A, MDA‐MB‐231	Compressive force induces increase of lamin A in MCF7 and MCF10A, decrease in MDA‐MB‐231	(Maremonti et al. 2022)
	Cancer, inflammation, atherosclerosis	Macrophages RAW264.7	Short decrease in lamin A/C with compressive forces	(Wang et al. 2025)
	Cancer	HeLa	Increase of lamin A/C in narrow channel compared to wide channel	(Wang et al. 2025)
Micropillar topography			Lamin A/C distribution change: higher at nuclear protrusions and lower in contact with micropillars	(Liang et al. 2024)
		HeLa	Lamin A colocalization with nanopillars	(Mitra et al. 2025)
Shear stress	Atherosclerosis	Endothelial cells	Lamin A degradation inhibition by snoRNA	(Bi et al. 2026)

3. Mechanical Regulation of Lamin A Abundance

A striking feature of lamin A biology is that lamin A/C abundance responds to a wide range of mechanical stimuli despite the complexity of its homeostasis. Because many studies investigating nuclear mechanobiology rely on antibodies or experimental approaches that do not discriminate between lamin A and lamin C, reported changes in lamin abundance frequently reflect combined lamin A/C levels. Accordingly, the term lamin A/C is used throughout this section when discussing the broader mechanobiology literature, whereas lamin A is reserved for processes specifically involving prelamin A processing and maturation.

Among the various aspects of lamin A biology, regulation of lamin A/C abundance represents the most extensively documented response to mechanical cues. Studies performed across diverse biological systems consistently demonstrate that mechanical cues are important regulators of lamin A/C abundance, underscoring the importance of nuclear mechanics in physiological and pathological processes including development, fibrosis, aging, immune responses, and cancer progression (Table 1).

Despite the diversity of mechanical stimuli reported to affect lamin A/C abundance, a common principle emerges from these studies. Mechanical signals ultimately modify the mechanical state of the nucleus, either through passive cell and nuclear deformations arising from tissue architecture, compression, confinement, or fluid shear stress, or through active force transmission mediated by actomyosin contractility and nucleo‐cytoskeletal coupling. Although the relative contributions of nuclear stress and nuclear strain remain unclear (Box 2), the available evidence suggests that lamin A/C abundance is regulated not by a specific mechanical stimulus per se, but rather by the resulting mechanical state of the nucleus.

BOX 2 | Interpreting mechanical perturbations in lamin mechanobiology regulation

Many studies correlate lamin A/C abundance with externally imposed mechanical variables such as substrate stiffness, confinement, compression, stretch, or fluid shear stress. However, these perturbations are not mechanically equivalent and can generate distinct stress and strain states within the nucleus, potentially triggering different responses at the level of the nuclear lamina. Definitions of stress and strain, together with examples of the principal mechanical modalities experienced by cells, are depicted below.

Literature discrepancies

Importantly, the mechanical state of the nucleus is not determined solely by the applied perturbation. Nuclear stress and strain also depend on the intrinsic mechanical properties of the cell and nucleus, including cytoskeletal organization, nucleo‐cytoskeletal coupling, chromatin compaction, and lamin A/C abundance itself. Consequently, identical experimental manipulations may generate markedly different nuclear mechanical states in different cellular contexts.

This concept is illustrated by the pioneering work of the Discher laboratory, which demonstrated that lamin A/C abundance scales with tissue stiffness across multiple tissues and cell types. Cells residing in soft tissues such as brain typically express low levels of lamin A/C and possess compliant nuclei, whereas cells from stiff tissues such as muscle or bone display higher lamin A/C levels and increased nuclear stiffness. Similar trends are observed during differentiation, with embryonic and stem‐like cells generally exhibiting softer nuclei and lower lamin A/C abundance than mature differentiated cells. These observations highlight an important conceptual challenge in lamin mechanobiology: externally applied mechanical perturbations cannot be directly equated with the mechanical state experienced by the nucleus. Consequently, the same perturbation may generate different levels of nuclear stress depending on the mechanical properties of the cell.

Future directions

This raises a fundamental unresolved question in the field: does lamin A/C abundance respond primarily to the applied force itself, to the resulting nuclear stress/strain, or to a combination of these parameters? Distinguishing between these possibilities will be essential for developing predictive models of lamin mechanoregulation and for understanding how cells integrate diverse mechanical inputs into a common nuclear response.

Extracellular matrix stiffness was among the first mechanical factors shown to influence lamin A/C abundance. In a landmark study, Swift et al. demonstrated that lamin A levels scale with tissue stiffness across a broad range of tissues and cell types, with lamin A/C abundance increasing in stiff tissues such as bone and decreasing in soft tissues such as brain or adipose tissue, whereas lamin B expression remains largely unaffected by tissue stiffness (Swift et al. 2013; Cho et al. 2019; Tan et al. 2024; Roy et al. 2025) (Table 1). These observations led to the proposal that lamin A/C abundance adapts to the mechanics of the cellular environment and contributes to the tuning of nuclear mechanical properties. Consistent with this concept, the relationship between stiffness and lamin A/C abundance has subsequently been observed in multiple contractile and non‐contractile cell types.

The relationship between mechanical cues and lamin A/C abundance extends beyond extracellular matrix stiffness. In epithelial tissues, local mechanical constraints arising from tissue architecture and apico‐basal compression dominate over extracellular matrix‐derived signals (Iyer et al. 2021). In these systems, nuclear morphology emerges as a strong predictor of lamin A/C levels, with flattened nuclei exhibiting higher levels of lamin A/C than spherical nuclei (Iyer et al. 2021; Maremonti et al. 2022). This phenomenon, which has also been observed in Drosophila epithelial tissues (Iyer et al. 2021), suggests that the coupling between nuclear geometry and lamin A/C expression/abundance is evolutionarily conserved.

Importantly, these observations indicate that lamin A/C abundance is influenced not only by tissue‐scale mechanical properties but also by local mechanical constraints acting directly on the nucleus. This distinction is particularly relevant because nuclear shape and deformation can vary substantially within a given tissue independently of extracellular matrix stiffness. Consistent with this idea, direct experimental manipulation of nuclear geometry through confinement, compression, or micropillar topography alters lamin A/C abundance (Maremonti et al. 2022; Wang et al. 2025; Liang et al. 2024; Mitra et al. 2025). In fibroblasts subjected to spatial confinement, changes in lamin A/C levels correlate with alterations in nuclear morphology (Srivastava et al. 2021). Similarly, mechanical compression in alveolar macrophages exposed to strong compressive forces within confined lung spaces induces cytoskeleton‐dependent downregulation of lamin A/C (Wang et al. 2025). This response has been associated with increased susceptibility to nuclear envelope rupture and DNA damage (Denais et al. 2016; Raab et al. 2016), and has been linked to pulmonary aging (Ba et al. 2025; De Silva et al. 2023). Comparable observations have been reported in macrophages cultured on nanotextured implant surfaces, where reduced nuclear size is accompanied by decreased lamin A/C level (Wang et al. 2025). Collectively, these studies reinforce the idea that lamin A/C abundance reflects the mechanical state of the nucleus across multiple biological scales.

While a positive relationship between mechanical stimulation and lamin A/C abundance predominates, notable exceptions have also been reported. For example, keloid fibroblasts exhibit reduced lamin A/C levels despite residing in a stiff extracellular environment, a phenotype associated with increased nuclear deformability and enhanced proliferation (Fu et al. 2024). Similarly, type II alveolar epithelial cells cultured on stiff matrices display reduced lamin A/C abundance (Ba et al. 2025). Although these observations appear to challenge the general relationship between mechanical cues and lamin A/C abundance, they highlight that lamin A/C levels are regulated by mechanisms that remain incompletely understood. Changes in lamin A (lamin A/C) abundance may arise from modulation of LMNA expression, alterations in prelamin A processing and maturation, or changes in protein turnover and degradation. Understanding how mechanical stimuli engage these regulatory pathways therefore represents a key challenge in lamin mechanobiology.

3.1. Mechanical Regulation of LMNA Gene Transcription

Given the extensive evidence demonstrating mechanical regulation of lamin A/C abundance, it is tempting to assume that these changes primarily arise through modulation of LMNA gene expression. Surprisingly, however, relatively few studies have directly investigated the transcriptional regulation of LMNA by mechanical stimulation. The link between gene transcription and lamin A/C protein accumulation has been questioned by Hasper et al. who reported an uncorrelation between LMNA transcripts and lamin A/C protein abundances (Hasper et al. 2024), suggesting that post‐transcriptional mechanisms may substantially contribute to lamin homeostasis. One of the major studies addressing transcriptional regulation was performed by Swift et al., who identified the presence of retinoic acid (RA) responsive elements within the LMNA gene locus and proposed that matrix elasticity acts upstream of the RA pathway, which in turn regulates transcription (Swift et al. 2013). Nevertheless, subsequent studies examining LMNA expression by RT‐qPCR reported little or no transcriptional regulation in response to mechanical stimulation (Wang et al. 2025; Ba et al. 2025; Bao et al. 2020). One notable exception was described in macrophages cultured on nanostructured titanium material, where lamin A/C transcripts were reduced as compared to smooth titanium surfaces (Fu et al. 2023). These observations suggest that transcriptional regulation alone is unlikely to account for the broad range of mechanically induced changes in lamin A/C abundance reported in the literature. In support of this notion, analysis of the first 1 kb of the lamin A promoter region shows a GC rich region devoid of TATA‐box and enriched in numerous SP1 binding sites with only one weak AP1 binding site, potentially linking LMNA transcription with mechanical stimulation. This is consistent with our previous work showing that nuclear envelope stretching is sufficient to induce AP1 entry into the nucleus and downstream gene regulation (Aureille et al. 2019).

The possibility that mechanical regulation occurs at post‐transcriptional levels is supported by studies in vascular smooth muscle cells exposed to chronic uniaxial cyclic stretch mimicking hypertensive conditions. While several studies reported reduced lamin A/C abundance under these conditions (Bao et al. 2020; Qi et al. 2016), Bao et al. demonstrated that the same hypertensive stress can also induce lamin A downregulation independently of LMNA transcript levels through induction of miR‐124‐3p (Bao et al. 2020). This regulatory microRNA suppresses LMNA translation without altering gene transcription and Lmna mRNA abundance, providing one of the first direct demonstrations that mechanical stimulation can regulate lamin A production at the translational level. Together, these findings suggest that transcriptional control contributes only partially to the mechanical regulation of lamin A/C abundance and highlight the potential importance of post‐translational regulatory mechanisms.

3.2. Mechanical Regulation of Lamin A Homeostasis Through Post‐Translational Modifications

Current evidence suggests that post‐translational modifications can act at two distinct stages of the lamin A life cycle. The first involves mature lamin A, where mechanically regulated post‐translational modifications have been implicated in controlling protein stability, turnover, and adaptation to changes in the mechanical environment. The second concerns prelamin A maturation. While the role of mechanical stimulation in regulating lamin A turnover has been relatively well documented, whether mechanical cues influence prelamin A processing remains largely unexplored. The emerging evidence discussed below suggests that this possibility deserves greater attention and may reveal a previously overlooked mechanism through which cells adapt lamin A homeostasis to mechanical stress.

3.2.1. Post‐Translational Control of Lamin A Stability and Degradation

Considering the long life attributed to lamin proteins (Hasper et al. 2024), and rapid responses observed for lamin regulation in response to mechanical stimulation, lamin A/C protein levels are most likely modulated at post‐translational level in human and mouse tissues. Lamin functions are regulated through diverse post‐translational modifications (PTMs) on lamins, including acetylation, methylation, O‐GlcNAcylation, phosphorylation, succinylation, SUMOylation, and ubiquitination (Murray‐nerger and Cristea 2021).

Among these mechanisms, phosphorylation‐dependent regulation of lamin A/C has emerged as one of the best‐characterized pathways linking mechanical stimulation to lamin homeostasis (Kochin et al. 2014). Initially associated with mitotic nuclear envelope breakdown (Dotie 1990), phosphorylation of lamin A/C at Ser22 and to a lesser extent at Ser392 promotes the redistribution of lamin A from the nuclear lamina into the nucleoplasm during interphase and influences the intranuclear mobility of lamin A (Kochin et al. 2014). Conversely, preventing phosphorylation increases lamina association (Torvaldson et al. 2015). The same phospho‐sites were implicated in the interphase responses to mechanical cues (Buxboim et al. 2014). The fraction of lamin‐A/C phosphorylated at Ser22 decreased concomitantly with increased nuclear spreading and levels of total lamin‐A/C, which were both otherwise promoted by stiff matrix (Buxboim et al. 2014). Importantly, changes in lamin A/C phosphorylation occur within minutes (Buxboim et al. 2014), suggesting a rapid mechanism by which cells can adjust nuclear mechanical properties independently of transcriptional regulation. Several studies support a model in which mechanical tension stabilizes lamin A/C, suppressing phosphorylation‐dependent degradation. During Drosophila development, physiological tissue compression induces stretching of lamin proteins, resulting in Ser22 dephosphorylation and lamin stabilization (Ba et al. 2025; Iyer et al. 2021). Together, these observations support the concept that mechanical forces can regulate lamin A/C abundance through modulation of protein stability. Among 20 phosphorylation sites identified during interphase, only a subset has been functionally characterized through advanced imaging approaches and single‐site mutagenesis (Kochin et al. 2014). Many highly conserved phosphorylation sites with high turn‐over remain unexplored, and their potential roles are still unknown. Notably, none of the identified phosphorylation sites matched the consensus motif for Rho‐associated protein kinase (ROCK) (Kochin et al. 2014).

Nevertheless, the relationship between mechanical stimulation, lamin phosphorylation, and protein abundance again can be context dependent on the type of mechanical stimulation and biological model (as discussed in Box 2). Using phosphoproteomic analysis of cyclically stretched skin epidermis stem cells (EPCs), Nava et al. (2020) observed a downregulation of LMNA phospho‐sites, including Ser22 and Ser392, without detectable changes in total lamin A/C protein levels. These findings suggest that mechanical regulation of lamin phosphorylation may contribute not only to protein turnover but also to additional aspects of lamin function and mechanoadaptation.

Mechanical regulation of lamin A stability may also involve non‐coding RNAs. In endothelial cells, laminar shear stress induces the expression of a circular snoRNA derived from exon 17 and intron 17 of the CNOT1 gene (sno‐circCNOT1), which is capable of binding lamin A protein and protects it from degradation (Bi et al. 2026). These findings reveal a novel mechanotransduction pathway that regulates lamin expression at the post‐translational level through the mechanically induced expression of snoRNA. Interestingly, mechanical induction of snoRNAs may represent a broader mechanotransduction pathway, as mechanical compression of epithelial monolayers has also been shown to stimulate extensive snoRNA production (Blonski et al. 2021).

Collectively, these studies establish post‐translational regulation of protein stability, localization (Hoffman et al. 2020), and degradation as an important mechanism through which mechanical forces control lamin A/C homeostasis. However, post‐translational modifications also act at an earlier stage of the lamin A life cycle through the maturation of prelamin A into lamin A. Although this processing pathway is highly conserved throughout vertebrate evolution, suggesting its important functional role, its physiological significance remains incompletely understood, raising important questions regarding its regulation and potential contribution to nuclear adaptation.

3.2.2. Post‐Translational Control of Prelamin A Maturation

Determining why prelamin A undergoes such extensive post‐translational processing has remained a longstanding question in lamin biology. Knock‐in mouse models expressing only mature lamin A exhibit discernible pathological phenotypes (Coffinier et al. 2010). Notably, in these models, the direct production of mature lamin A induced a normal localization of the protein to the nuclear periphery in tissues but showed an increased nucleoplasmic distribution in cultured fibroblasts, a feature associated with nuclear shape abnormalities when compared to wild‐type fibroblasts (Coffinier et al. 2010). These observations suggest that prelamin A processing contributes not only to the generation of mature lamin A but also to its proper spatial organization within the nucleus. This raises the possibility that alterations in prelamin A maturation influence nuclear mechanoadaptation through mechanisms that extend beyond bulk nuclear stiffness. Consistent with this notion, Coffinier and colleagues found that bypassing prelamin A maturation did not measurably alter global nuclear stiffness under 20% uniaxial stretch, suggesting that any functional consequences of alternative processing routes are likely to involve subtler regulatory mechanisms. Altogether, the complex processing of prelamin A to lamin A could represent a fundamental regulatory switch to convert a protective pathway into an ageing pathway, as speculated by Cenni et al. Mechanical stimulation being one of many possible stress inducers in cells (Cenni et al. 2020).

Among the different maturation steps, protein farnesylation appears to play a particularly important role in lamin‐mediated mechanical adaptation. The role of protein prenylation has been increasingly recognized in mechanotransduction as it profoundly affects the functions of key mechanotransduction proteins such as Rho, Ras, and lamins. Farnesylation was shown to increase protein hydrophobicity and membrane affinity (Chen et al. 2025). In the case of prelamin A, farnesylation constitutes an essential step of the maturation process, which ends up by the removal of the farnesylated C‐terminus by ZMPSTE24 to generate mature lamin A. Evidence for the importance of this step comes primarily from the pathological context of Hutchinson–Gilford progeria syndrome (HGPG), a rare disorder in which premature termination of prelamin A processing (aborted before the final ZMPSTE24‐mediated cleavage) leads to accumulation of permanently farnesylated progerin (Schreiber and Kennedy 2013) and accelerating aging (McClintock et al. 2007). Progerin arises from a constitutively activated cryptic splice donor site due to a specific ultra‐rare point mutation in LMNA. HGPS cells display alterations in nuclear morphology (Paradisi et al. 2005), impaired adaptation to mechanical stress (Srivastava et al. 2026; Verstraeten et al. 2008), and increased apoptosis under mechanical stress (Danielsson et al. 2022).

Importantly, inhibition of farnesylation improves both nuclear morphology and cellular adaptation to mechanical forces (Gordon et al. 2016), whereas complete deficiency of ZMPSTE24, which abolishes the conversion of farnesylated prelamin A into mature lamin A, leads to restrictive dermopathy, a severe neonatal lethal progeroid syndrome. This observation highlights the essential role of this processing pathway in normal development (Moulson et al. 2005). Consistent with the severe phenotypes observed in HGPS and ZMPSTE24‐deficient models (Moulson et al. 2005), progerin and farnesylated prelamin A were shown to trigger similar abnormalities in lamin meshwork organization, nuclear morphology, and nuclear envelope integrity (Kim et al. 2025). These findings highlight the impact of farnesylation on lamin‐mediated cellular mechanical adaptability under pathological conditions (Chen et al. 2025). Interestingly, the relevance of this pathway may extend beyond rare progeroid syndromes, as low levels of progerin are also produced in normal human cells and tissues and progressively accumulate during aging (McClintock et al. 2007). Moreover, progressive telomere damage during cellular senescence has been shown to promote progerin production (Cao et al. 2011), suggesting that the accumulation of farnesylated lamin species may contribute to age‐associated changes in nuclear mechanics and mechanoadaptation. How farnesylation regulates these processes in other contexts remains an area for future exploration. Collectively, these observations demonstrate that perturbations of prelamin A processing profoundly alter nuclear architecture and cellular responses to mechanical stress, highlighting the functional importance of the maturation pathway for nuclear mechanoadaptation.

While pathological models establish the importance of prelamin A processing for nuclear mechanics, they do not explain whether the maturation pathway itself can be regulated by mechanical cues. Several observations nevertheless suggest that the final ZMPSTE24‐dependent cleavage may represent a mechanically sensitive step.

In vitro assays and characterization of the farnesylation‐dependent prelamin A endoprotease ZMPSTE24 have demonstrated that only farnesylated prelamin A can be cleaved by the endoprotease, showing that lipidation and membrane association are prerequisites for processing (Sinensky et al. 1994). Moreover, while determining the structure of ZMPSTE24 based on crystallization, Quickley et al. (Quickley et al. 2013) describe the entry route of the substrate to require farnesylation to be embedded within the membrane. Two groups (Yang et al. 2011; Diver et al. 2018) determined also the structure of prokaryotic and eukaryotic ICMT, localizing in both studies the entry route of substrate proteins to the inner leaflet of the membranes.

The importance of membrane association is further supported by observations of prelamin A intracellular localization. Studies dating back to the early 1990s showed that microinjected recombinant prelamin A obtained from bacterial overexpression transiently accumulates in nucleoplasmic foci before its incorporation into the peripheral nuclear lamina (Goldman et al. 1992). More recently, GFP‐tagged prelamin A was also reported to accumulate in nucleoplasmic foci following the treatment of cells with farnesyltransferase inhibitors (Barrowman et al. 2008; Casasola et al. 2016). These observations suggest that access of prelamin A to membrane‐associated processing machinery and assembly pathways is tightly regulated and may represent a critical step controlling its maturation. In this context, mechanical cues capable of altering lamin assembly, nuclear envelope organization, or the partitioning of lamin proteins between nucleoplasmic and peripheral pools could potentially influence the efficiency of prelamin A processing.

ZMPSTE24, RCE, and ICMT are transmembrane enzymes involved in prelamin A maturation and localized to the endoplasmic reticulum and nuclear envelope (Barrowman et al. 2008). This localization may be particularly significant in the context of mechanical stimulation known to alter nuclear envelope tension (Aureille et al. 2019), curvature (Aureille et al. 2017), and dynamics (Chu et al. 2017). Interestingly, systematic mutational analysis of the prelamin A tail shows a potential impact on cleavage efficiency by ZMPSTE24 (Wood et al. 2020). This observation suggests that structural parameters influence processing efficiency and raises the possibility that mechanically induced changes in nuclear envelope tension or curvature could modulate the accessibility or activity of the maturation machinery.

Beyond these structural considerations, emerging evidence suggests that mechanical environments may also influence the expression of the processing machinery itself. In patients with osteoarthritis, chondrocytes are subjected to an abnormal mechanical compressive environment (Kong et al. 2023). When investigating the molecular mechanism underlying chondrocyte senescence caused by mechanical overloading, Kong et al. showed that compression resulted in a lower expression of ZMPSTE24 associated with nuclear membrane blebbing and senescence (Kong et al. 2023). Similarly, metabolic‐associated steatotic liver disease (MASLD), a condition associated with profound alterations in tissue mechanics and nuclear envelope organization (Schinderle et al. 2025), is accompanied by a downregulation of ZMPSTE24 and accumulation of prelamin (Schinderle et al. 2025).

Collectively, the available evidence suggests that prelamin A maturation may represent a previously underexplored mechanosensitive process. Although direct evidence that mechanical cues regulate prelamin A processing is still lacking, several observations point toward this possibility, including the dependence of ZMPSTE24 activity on membrane‐associated substrates, the sensitivity of cleavage efficiency to substrate geometry, and the emerging links between altered mechanical environments and ZMPSTE24 expression. Exploring this hypothesis may reveal a new layer of lamin mechanobiology and provide fresh insight into how cells adapt nuclear architecture and function to mechanical stress.

4. Conclusions and Perspectives

Lamin A/C has long been recognized as a central regulator of nuclear mechanics and mechanotransduction. The evidence reviewed here further supports the reciprocal concept that lamin A homeostasis is itself regulated by mechanical cues. Mechanical stimulation influences lamin A abundance through multiple levels of regulation, including transcription, translation, protein turnover, subcellular localization, supramolecular organization, and post‐translational modifications. Together, these observations suggest that lamin A homeostasis is dynamically tuned in response to changing mechanical environments rather than being maintained through a constitutive biosynthetic pathway.

Among these regulatory mechanisms, prelamin A maturation remains one of the least explored. The evidence reviewed here raises the possibility that lamin A abundance and homeostasis are regulated by mechanical cues not only through transcription, translation, and degradation, but also at the level of prelamin A processing. Although several observations support this hypothesis, direct demonstration that mechanical forces regulate the efficiency, kinetics, or spatial organization of prelamin A maturation remains lacking.

Importantly, understanding whether mechanical forces regulate prelamin A processing is not only a technical challenge but also a biologically relevant question. Prelamin A maturation has traditionally been viewed as a constitutive biosynthetic pathway required for the generation of mature lamin A. However, emerging evidence suggests that specific prelamin A intermediates can accumulate transiently under cellular stress conditions and actively participate in adaptive responses, including the regulation of nuclear homeostasis and DNA damage signaling (Capanni et al. 2022). These observations raise the possibility that prelamin A processing may function as a regulatory node rather than a passive maturation pathway.

A major challenge stems from the complexity of the maturation process itself. Prelamin A processing involves multiple sequential enzymatic steps occurring at membrane‐associated compartments and generating transient intermediates that are difficult to detect and quantify. Consequently, most available experimental approaches assess the consequences of impaired processing rather than the dynamics of the maturation process itself. Pharmacological inhibitors of farnesylation or ZMPSTE24 activity have proven valuable for perturbing the pathway and studying the resulting effects on nuclear architecture and mechanics. However, these approaches provide limited information regarding how environmental mechanical cues influence the rate, efficiency, or spatial organization of prelamin A processing under physiological conditions.

Proteomic approaches have also contributed relatively little to this question. One limitation is that prelamin A maturation is characterized by subtle and transient modifications within the C‐terminal region of the protein, generating uncharged lipophilic peptides that are difficult to detect using conventional mass spectrometry. In addition, membrane‐associated farnesylated intermediates are often underrepresented in standard proteomic workflows, making quantitative analysis of processing dynamics particularly challenging. Among emerging approaches, click‐chemistry‐based detection of farnesylated proteins appears especially promising (Schinderle et al. 2025). Such methods could potentially quantify global changes in protein farnesylation and, when combined with microscopy‐based approaches, provide spatial information on the intracellular distribution of farnesylated prelamin A species. More broadly, the development of tools capable of distinguishing the different maturation intermediates of prelamin A will be essential for determining whether mechanical forces regulate lamin A biogenesis through this pathway.

Several fundamental questions therefore remain unanswered. Does nuclear envelope curvature regulate the activity of the prelamin A processing machinery? Can membrane geometry or cellular tension modulate the efficiency of farnesylation, proteolytic cleavage, or carboxymethylation? More broadly, do mechanical cues influence the balance between canonical and alternative processing routes, thereby regulating the ratio of prelamin A intermediates to mature lamin A and ultimately the assembly and stability of the nuclear lamina?

Ultimately, the challenge is no longer to define the individual steps of lamin A biogenesis, but to understand how mechanical cues coordinate these regulatory processes to adapt the nuclear lamina to changing physical environments.

Conflicts of Interest

The authors declare no conflicts of interest.

Use of Generative AI and AI‐Assisted Technologies in the Writing Process

OpenAI's GPT‐5 was used under the authors' supervision to assist with language refinement. No AI‐generated scientific content, data, interpretations, or unverified citations were included in the final manuscript. The authors take full responsibility for the accuracy, integrity, and originality of the manuscript.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.