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The genetic causality between cathepsin levels and autoimmune diseases (ADs) bidirectionally was investigated and the associated cancer risk was explored with Mendelian randomization. Mendelian randomization analyses were used to explore causal associations between cathepsin and 14 ADs. The final results came from a meta-analysis of two datasets to get a robust result. Furthermore, the potential carcinogenic effects of reduced cathepsin levels were explored. Sensitivity analyses were used to evaluate the robustness of the results. Based on the Mendelian randomization analysis, it was found that lower levels of specific cathepsins were associated with reduced risk of ADs. Reduced cathepsin E levels were linked to decreased susceptibility to psoriasis and a potential reduction in breast cancer risk. Reduced cathepsins G and L2 showed an inhibitory effect on psoriasis without increasing cancer risk. These results emphasized the genetic causal connection between cathepsin and ADs. Targeting cathepsins may be beneficial in treating ADs, but potential oncogenic effects must be considered to provide a basis for safer therapeutic strategies. [ABSTRACT FROM AUTHOR]

Lysosomes play a crucial role in various intracellular pathways as their final destination. Various stressors, whether mild or severe, can induce lysosomal membrane permeabilization (LMP), resulting in the release of lysosomal enzymes into the cytoplasm. LMP not only plays a pivotal role in various cellular events but also significantly contributes to programmed cell death (PCD). Previous research has demonstrated the participation of LMP in central nervous system (CNS) injuries, including traumatic brain injury (TBI), spinal cord injury (SCI), subarachnoid hemorrhage (SAH), and hypoxic-ischemic encephalopathy (HIE). However, the mechanisms underlying LMP in CNS injuries are poorly understood. The occurrence of LMP leads to the activation of inflammatory pathways, increased levels of oxidative stress, and PCD. Herein, we present a comprehensive overview of the latest findings regarding LMP and highlight its functions in cellular events and PCDs (lysosome-dependent cell death, apoptosis, pyroptosis, ferroptosis, and autophagy). In addition, we consolidate the most recent insights into LMP in CNS injury by summarizing and exploring the latest advances. We also review potential therapeutic strategies that aim to preserve LMP or inhibit the release of enzymes from lysosomes to alleviate the consequences of LMP in CNS injury. A better understanding of the role that LMP plays in CNS injury may facilitate the development of strategic treatment options for CNS injury. [ABSTRACT FROM AUTHOR]

• Cystatin C is an extracellular tight-binding inhibitor of cysteine cathepsins. • Human cystatin C (hCC) is a relevant marker of glomerular filtration rate (GFR) • hCC is overexpressed during cardiac, lung or liver fibrosis. • hCC could promote matrix deposition by inhibition of proteolytic enzymes. • hCC has been proposed as a potential biomarker of fibrosis. Human cystatin C (hCC), which has a pervasive distribution within body fluids and is ubiquitously expressed by numerous cells and tissues, is a highly potent extracellular inhibitor of cysteine proteases. Besides measurement of serum creatinine, which is the most widely used technique for appraising glomerular filtration rate (GFR), hCC has emerged as a relevant GFR biomarker, because its quantification in serum is less sensitive to interferences with factors such as age, muscle mass or diet. Moreover, there are growing body of evidence that hCC overexpression and/or oversecretion, which is primarily driven by TGF-β1, occur during fibrogenesis (cardiac, liver, oral, and lung fibrosis). Even though molecular mechanisms and signaling pathways governing the regulation of hCC remain to be deciphered more acutely, current data sustain that hCC expression relates to myofibrogenesis and that hCC could be a specific and valuable biomarker of fibrotic disease. [ABSTRACT FROM AUTHOR]