Protein Ubiquitination Modification in Pulmonary Fibrosis

Pulmonary fibrosis (PF) is a chronic, progressive fibrotic interstitial lung disease characterized by a high incidence and mortality rate, which encompasses features, such as diffuse alveolar inflammation, invasive fibroblast activation, and uncontrolled extracellular matrix (ECM) deposition. Beyond the local pathological processes, PF can be better understood in light of interorgan communication networks that are involved in its progression. Notably, pulmonary inflammation can affect cardiovascular, renal, hepatic, and neural functions, highlighting the importance of understanding these systemic interactions. Posttranslational modifications play a crucial role in regulating protein function, localization, stability, and activity. Specifically, protein ubiquitination modifications are involved in PF induced by various stimuli, involving a range of ubiquitin-modifying enzymes and substrates. In this review, we provide an overview of how E3 ubiquitin ligases and deubiquitinating enzymes (DUBs) modulate PF through several signaling pathways, such as TGF-β, Wnt, metabolic activity, aging, ferroptosis, endoplasmic reticulum stress, and inflammatory responses. This perspective includes the role of ubiquitin-proteasome systems in interorgan communication, affecting the progression of PF and related systemic conditions. Additionally, we also summarize the currently available therapeutic compounds targeting protein ubiquitination-related enzymes or ubiquitination substrates for the treatment of PF. Understanding the interplay between ubiquitination and interorgan communication may pave the way for novel therapeutic strategies.