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Background <p>Chemical injury of the cornea, particularly alkali-induced corneal injuries, triggers a self-amplifying cascade of inflammation, extracellular matrix disruption, and pathological neovascularization that often resists conventional therapy. Transglutaminase-2 (TG2) is a calcium-dependent enzyme whose activation in injured tissues orchestrates crosslinking of matrix proteins and modulation of inflammatory signaling, positioning it as a mechanistic hub in tissue damage.</p> Main text <p>Here we review the molecular and cellular mechanisms underpinning TG2’s role in corneal injury, focusing on its compartment-specific functions in intracellular stress responses, cell–matrix adhesion dynamics, and extracellular matrix stabilization. We also synthesize evidence from preclinical models indicating that injury-induced TG2 activity generates a microenvironment permissive to targeted therapeutic anchoring. Building on this concept, we describe the design and biological rationale of a genetically engineered fusion protein composed of a TG2 substrate domain (cementoin) linked to secretory leukocyte protease inhibitor (SLPI), enabling covalent anchoring to TG2-rich injured tissue. Our preclinical studies demonstrate that this fusion protein improves local tissue retention, modulates inflammatory signaling, reduces protease activity, and attenuates pathological neovascularization in alkali-induced corneal damage.</p> Conclusions <p>Exploiting injury-generated enzymatic activity, rather than inhibiting isolated downstream pathways, represents a novel therapeutic paradigm. The cementoin–SLPI fusion protein exemplifies a context-dependent strategy to achieve spatially restricted modulation of inflammation and tissue remodeling. These mechanistic insights and translational perspectives lay the groundwork for clinical evaluation of TG2-targeted biologics in severe ocular surface disease.</p>

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Targeting injury-induced transglutaminase-2 activity with a cementoin–SLPI fusion protein: a novel therapeutic strategy for alkali-induced corneal injury

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月27日

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  • Juan Pablo Salica,
  • Constanza Potilinski,
  • Gustavo Ortiz,
  • Diego Guerrieri,
  • Paulo C. Maffia,
  • Eduardo Chuluyan,
  • Juan E. Gallo

摘要

Background

Chemical injury of the cornea, particularly alkali-induced corneal injuries, triggers a self-amplifying cascade of inflammation, extracellular matrix disruption, and pathological neovascularization that often resists conventional therapy. Transglutaminase-2 (TG2) is a calcium-dependent enzyme whose activation in injured tissues orchestrates crosslinking of matrix proteins and modulation of inflammatory signaling, positioning it as a mechanistic hub in tissue damage.

Main text

Here we review the molecular and cellular mechanisms underpinning TG2’s role in corneal injury, focusing on its compartment-specific functions in intracellular stress responses, cell–matrix adhesion dynamics, and extracellular matrix stabilization. We also synthesize evidence from preclinical models indicating that injury-induced TG2 activity generates a microenvironment permissive to targeted therapeutic anchoring. Building on this concept, we describe the design and biological rationale of a genetically engineered fusion protein composed of a TG2 substrate domain (cementoin) linked to secretory leukocyte protease inhibitor (SLPI), enabling covalent anchoring to TG2-rich injured tissue. Our preclinical studies demonstrate that this fusion protein improves local tissue retention, modulates inflammatory signaling, reduces protease activity, and attenuates pathological neovascularization in alkali-induced corneal damage.

Conclusions

Exploiting injury-generated enzymatic activity, rather than inhibiting isolated downstream pathways, represents a novel therapeutic paradigm. The cementoin–SLPI fusion protein exemplifies a context-dependent strategy to achieve spatially restricted modulation of inflammation and tissue remodeling. These mechanistic insights and translational perspectives lay the groundwork for clinical evaluation of TG2-targeted biologics in severe ocular surface disease.