{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPSMA3, a critical α‐subunit of the 20S proteasome, plays central roles in regulating protein turnover via a ubiquitin‐independent degradation pathway. For example, the hepatitis C virus F protein binds directly to the PSMA3 subunit, leading to its dose‐dependent degradation and suggesting that PSMA3 is pivotal for controlling the stability of certain viral regulatory proteins and, by extension, cellular homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its core function in proteolysis, PSMA3 engages in intricate protein–protein interactions that extend its influence into nuclear processes. Systematic analyses have revealed that PSMA3 interacts with multiple proteins involved in mRNA metabolism—including splicing factors—thereby implicating it in the regulation of post‐transcriptional gene expression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic epidemiology studies further underscore the significance of PSMA3 by demonstrating that single nucleotide polymorphisms within the PSMA3 gene are significantly associated with increased susceptibility to type 1 diabetes mellitus. This finding suggests that alterations in PSMA3 function may impact both proteostasis and immune regulatory pathways."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its intracellular roles, PSMA3 has been implicated in the extracellular regulation of protein distribution and tissue homeostasis. Notably, PSMA3 interacts with ameloblastin—a protein essential for enamel formation—and mediates its proteolytic processing, which appears to contribute to the spatial organization of the extracellular matrix and to biomineralization processes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPSMA3 also emerges as an important factor in cancer biology with diagnostic and prognostic implications. Elevated levels of PSMA3 in secretomes and patient plasma have been observed in cholangiocarcinoma, positioning it as a promising biomarker for early diagnosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Moreover, the long noncoding RNA PSMA3‐AS1—an antisense transcript related to PSMA3—has been linked to altered proteasome inhibitor sensitivity in multiple myeloma"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "and to poor prognosis in ovarian cancer by promoting oncogenic signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " In esophageal squamous cell carcinoma, overexpression of PSMA3 is further correlated with increased cancer stemness and reduced infiltration by CD8⁺ T lymphocytes through the CCL3/CCR5 axis, highlighting its role in tumor immune escape."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Kamile Yuksek, Wen-Ling Chen, David Chien, et al. 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