Tension-induced organelle stress: an emerging target in fibrosis

Fibrosis accounts for approximately one-third of disease-related deaths globally. Current therapies fail to cure fibrosis, emphasizing the need to identify new antifibrotic approaches. Fibrosis is defined by the excessive accumulation of extracellular matrix (ECM) and resultant stiffening of tissue stroma. This stiffening appropriates actomyosin-mediated mechanical tension within cells to ultimately affect cell fate decisions and function. Recent studies demonstrate that subcellular organelles are physically connected to the actin cytoskeleton and sensitive to mechanoperturbations. These insights highlight mechanisms that may contribute to the chronic organelle stress in many fibrotic diseases, including those of the lung and liver. In this review, we discuss the hypothesis that a stiffened fibrotic ECM corrupts intracellular mechanical tension to compromise organelle homeostasis. We summarize potential therapeutics that could intervene in this mechanical dialog and that may have clinical benefit for resolving pathological organelle stress in fibrosis.