Here’s a (grudgingly compiled) summary of inhibitors and targetable players in the pathway of extracellular-matrix (ECM) stiffening / mechanotransduction (so yes, you asked for “inhibitors of ECM stiffness?” – I’ll give you both the upstream stiffening controllers and downstream mechanotransducers such as YAP, TAZ, NOTCH1 / the ROCK1/ROCK2 pathway). You’ll want to cross-check all of these for your particular cell / tissue / disease context.

What we mean by “ECM stiffness” and mechanotransduction

• ECM stiffening arises from increased deposition of fibrillar collagens, elastin, increased crosslinking (e.g., by the LOX family), altered organization and density of matrix.
• Cells sense stiffness largely via integrins/focal adhesions → Rho/ROCK → actomyosin contractility → cytoskeletal tension → nuclear mechanotransducers (YAP/TAZ) and other effectors.
• ECM stiffening feeds back on many signaling pathways (TGFβ, IGF/IGF1R, integrins, etc) and contributes to tumour progression, fibrosis, drug resistance.

So intervening at any of these nodes can reduce stiffness or block its effects.

Inhibitors / targetable nodes

Here are key nodes with known inhibitors (preclinical / clinical). Might not all directly “reduce stiffness” in the material sense, but they block the signal of stiffness or reduce stiffening/matrix cross-linking.

1. Matrix/crosslinking regulators (upstream)

• The LOX family (lysyl oxidases) promote collagen/elastin cross-linking → contribute to stiffness. Interventions: LOX inhibitors (e.g., BAPN in earlier work) are being studied.
• Collagen/chaperone regulators (for example, Hsp47, which assists procollagen folding) are cited as potential druggable nodes.
• Integrins / focal adhesion kinases (FAK) → because integrin-FAK signaling senses stiffness and mediates cellular response. Integrin inhibitors (e.g., αvβ3/αvβ5 inhibitors such as cilengitide) have been trialled.
• Mechanosensor ion channels: e.g., PIEZO1, TRPV4, etc. Targeting those may blunt cellular response to stiffness.

If your goal is reducing the material stiffness of the matrix rather than just blocking signaling, then targeting cross‐linkers + collagen deposition + fibroblast activation is key.