Abstract: TRULI, also referred to as Lats-IN-1, is a pharmacological inhibitor of the Large Tumor Suppressor 1 and 2 (LATS1/2) kinases, which are core components of the highly conserved Hippo signaling pathway. By inhibiting LATS1/2, TRULI prevents the phosphorylation and subsequent degradation of Yes-associated protein (YAP), facilitating its nuclear translocation and the activation of genes involved in cell proliferation, survival, and plasticity. In the context of regenerative medicine, TRULI has demonstrated significant therapeutic potential and complex, context-dependent effects across different tissue types. In cardiac models, it promotes cardiomyocyte proliferation, reduces apoptosis, and improves heart function following myocardial infarction. In dental tissues, it induces proliferation and colony formation in dissociated primary ameloblasts. Conversely, in corneal tissue, TRULI inhibits the de-differentiation of corneal epithelial cells into limbal epithelial stem cells, highlighting that YAP activation is not universally pro-regenerative. This review synthesizes the current literature on TRULI, detailing its pharmacological activity, molecular mechanisms, limitations, and future perspectives in regenerative medicine.
1. Introduction
Tissue homeostasis and injury repair rely heavily on the activity of resident somatic stem cells and the precise regulation of cellular plasticity, proliferation, and differentiation [2]. The Hippo signaling pathway is an evolutionarily conserved kinase cascade that plays a critical role in organ size control, tissue regeneration, and repair [1]. The core of this pathway involves the LATS1/2 kinases, which negatively regulate the downstream transcriptional co-factors YAP and TAZ. When the Hippo pathway is active, LATS1/2 phosphorylate YAP, leading to its cytoplasmic sequestration and degradation. Conversely, when LATS1/2 are inhibited, unphosphorylated YAP translocates to the nucleus to drive the expression of genes that promote cell proliferation and survival [1][2].
TRULI (also widely identified in the literature as Lats-IN-1) is a small-molecule inhibitor specifically targeting LATS1/2 kinases [1][2][3]. By pharmacologically blocking LATS1/2, TRULI provides a translational approach to modulating the Hippo/YAP pathway. Recent studies have explored the application of TRULI in regenerative medicine, investigating its capacity to stimulate cardiac repair post-myocardial infarction (MI) [1], induce plasticity in differentiated dental epithelial cells [2], and influence the de-differentiation of corneal epithelial cells [3].
2. Pharmacological Activity
The pharmacological effects of TRULI (Lats-IN-1) in regenerative medicine are highly tissue-specific, demonstrating both pro-regenerative and inhibitory effects depending on the cellular context.
Cardiac Regeneration: In a murine model of myocardial infarction, intraperitoneal administration of Lats-IN-1 (1 mg/kg/d) significantly alleviated post-MI cardiac dysfunction. Echocardiographic assessments revealed enhanced ejection fraction (EF%) and fractional shortening (FS%), alongside reduced left ventricular internal dimensions and volumes, indicating an attenuation of pathological heart remodeling [1]. Furthermore, Lats-IN-1 treatment notably reduced the infarct size and cardiac fibrosis. It actively promoted the proliferation of cardiomyocytes in both the infarcted and remote zones of the heart, as evidenced by increased markers such as PH3, Aurora B kinase, and BrdU incorporation [1].
Dental Tissue Plasticity: In the adult mouse incisor, differentiated ameloblasts typically resist YAP-driven proliferation in vivo. However, when primary cells from the ameloblast region were dissociated and cultured as single cells in a 3D Matrigel environment, treatment with TRULI (10 μM) significantly enhanced their proliferation. The LATS inhibitor induced spheroid colony formation in these differentiated cells to a level comparable to that of progenitor cells, demonstrating that TRULI can unlock cellular plasticity when cells are removed from the contact inhibition and signaling constraints of intact tissue [2].
Corneal Epithelial De-differentiation: In the cornea, the regeneration of limbal epithelial stem cells (LESCs) after injury relies on the de-differentiation of committed corneal epithelial cells (CECs). Interestingly, the de-differentiation process requires a low level of YAP activity. When TRULI (20 μM) was administered topically to the cornea following LESC ablation, it indirectly activated YAP and consequently inhibited the de-differentiation of CECs into functional LESCs. This contrasts with the YAP-TEAD inhibitor verteporfin (VTP), which promoted the de-differentiation process [3].
3. Molecular Mechanism of Action
TRULI functions as a direct inhibitor of the LATS1 and LATS2 kinases. The molecular consequences of this inhibition vary by tissue type but fundamentally revolve around the stabilization and nuclear accumulation of YAP.
In myocardial tissue, Lats-IN-1 treatment decreases the phosphorylation levels of Lats1/2 (p-Lats1/2) and subsequently reduces the ratio of phosphorylated YAP (p-YAP) to total YAP. This indicates the successful activation of YAP. Alongside YAP activation, Lats-IN-1 modulates apoptotic signaling pathways. It significantly decreases the expression of the pro-apoptotic marker Bax and reduces the levels of apoptosis-executioner proteins Caspase 3 and Caspase 9. This dual mechanism—driving YAP-mediated proliferation and suppressing apoptosis—protects cardiomyocytes from death and mitigates abnormal cell enlargement (hypertrophy) following ischemic injury [1].
In dental and corneal epithelia, the mechanism highlights the importance of the tissue microenvironment. In dental cells, LATS1/2 normally serve as gatekeepers that limit the proliferative state of transit-amplifying progenitors and maintain ameloblasts in a differentiated state. TRULI removes this LATS-mediated suppression, allowing YAP to drive proliferation, provided that local inhibitory signals (like contact inhibition) are disrupted via cell dissociation [2]. In the corneal epithelium, YAP activity is naturally higher in peripheral and central cells compared to limbal cells. Following limbal injury, YAP is transiently activated but must return to a low baseline to allow CECs to de-differentiate into LESCs. By inhibiting LATS, TRULI forces sustained YAP activation, which blocks the cellular reprogramming required for LESC regeneration [3].
4. Structure-Activity Relationship (SAR)
The provided literature focuses exclusively on the in vivo and in vitro biological applications of TRULI (Lats-IN-1) in various regenerative models. There is no data provided regarding the chemical structure, functional group modifications, binding affinity variations, or Structure-Activity Relationship (SAR) profiles of TRULI or its analogs [1][2][3].
5. Current Limitations
Several limitations currently restrict the broader application of TRULI in regenerative medicine:
Lack of Dose-Response Data: In cardiac regeneration studies, TRULI was administered at a single dose (1 mg/kg/d). The absence of comprehensive dose-response analyses makes it challenging to ascertain the optimal therapeutic window, efficacy at varying concentrations, and the long-term safety profile required for clinical translation [1].
Context-Dependent Efficacy: TRULI does not act as a universal "regenerative switch." In intact dental tissues, YAP overactivation via LATS inhibition is insufficient to induce proliferation in differentiated ameloblasts due to the overriding influence of the tissue microenvironment and contact inhibition [2]. Furthermore, in the cornea, TRULI actively prevents the de-differentiation of CECs into stem cells, proving that sustained YAP activation can be detrimental to certain types of cellular reprogramming and tissue repair [3].
6. Future Perspectives
The use of TRULI as a pharmacological tool opens several avenues for future research in regenerative medicine. For cardiovascular applications, further investigations must prioritize dose-optimization studies and rigorous safety profiling to advance Lats-IN-1 as a viable therapeutic strategy for patients with heart failure and cardiomyocyte loss [1].
In craniofacial and dental research, future studies should focus on elucidating how the local signaling microenvironment (e.g., BMP4, FGF, EGF) and contact inhibition interact with the Hippo pathway. Understanding these dynamics could allow researchers to safely combine TRULI with other agents to manipulate stem cell proliferation and differentiation for bioengineered dental tissues [2].
Finally, the complex role of YAP in cellular plasticity requires deeper mapping of its upstream inputs (such as mechanotransduction and stromal stiffness) and downstream transcriptional targets. Unraveling this network will be crucial for determining exactly when and where LATS inhibitors like TRULI should be applied, ensuring they promote rather than hinder tissue-specific regeneration [3].
