{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Leukemia inhibitory factor (LIF) is a highly pleiotropic cytokine of the interleukin‐6 family that functions in multiple biological contexts ranging from stem cell self‐renewal and tissue regeneration to bone remodeling and cancer. In mouse embryonic stem cells, LIF is essential for maintaining “stemness” by activating the STAT3 pathway, which in turn sustains pluripotency and self‐renewal (see."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": " In contrast, despite being able to induce STAT3 phosphorylation in human embryonic stem cells, LIF cannot prevent their differentiation, highlighting a species‐specific divergence in stem cell regulation."}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its role in pluripotency, LIF contributes to skeletal homeostasis. It participates in the regulation of bone resorption by influencing the expression of key osteoclastogenic factors—such as receptor activator of NF‐κB ligand (RANKL) and osteoprotegerin (OPG)—as demonstrated in neonatal calvarial models."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Furthermore, LIF functions as one of several IL-6 type cytokines produced by activated monocytes/macrophages to promote osteoblast differentiation and matrix mineralization."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the realm of cancer biology, LIF signaling displays context-dependent roles. Its receptor (LIFR) has been identified as a metastasis suppressor in breast cancer by engaging Hippo pathway kinases to inactivate YAP, thereby curbing metastatic progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Moreover, in pancreatic cancer the IL-6/LIF-gp130 signaling cascade contributes to robust STAT3 activation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ", and in triple-negative breast cancer, noncoding RNA networks regulate LIF expression to promote tumor progression via the LIF/STAT3 axis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " In addition, when combined with IL-6, LIF in the tumor microenvironment can steer monocyte differentiation into tumor-associated macrophages."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n LIF also influences neural repair processes. For example, after spinal cord injury, the normal astrocytic response—at least in part mediated by cytokines including LIF—is altered in EphA4-deficient mice, which exhibit reduced gliosis and improved axonal regeneration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, as underscored by recent reviews, LIF’s diverse actions extend to roles in maternal receptivity, placental formation, and nervous system development."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": " In inflammatory settings such as inflammatory bowel disease, IL-22 stimulation of colonic subepithelial myofibroblasts induces the expression of several cytokines—including LIF—thereby contributing to local proinflammatory signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Together, these findings illustrate that LIF’s function is highly context dependent. Its ability to modulate cell fate decisions, orchestrate immune responses, and regulate tissue homeostasis and repair makes it a critical molecule with varied—and sometimes opposing—effects in development, disease, and regeneration.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Qi Long Ying, Jennifer Nichols, Ian Chambers, et al. 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