{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:04:08Z","timestamp":1790697848509,"version":"4.1.0"},"reference-count":36,"publisher":"BMJ","issue":"2","license":[{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"unspecified","delay-in-days":61,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82302042"],"award-info":[{"award-number":["82302042"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Sanming Project of Medicine in Shenzhen","award":["SZSM202111006"],"award-info":[{"award-number":["SZSM202111006"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["Lupus Sci Med"],"accepted":{"date-parts":[[2026,8,4]]},"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To investigate whether MLKL crotonylation is associated with tubular autophagy\u2013lysosome pathway homeostasis in lupus nephritis (LN) and to explore its relationship with RAB1A\u2013mechanistic target of rapamycin (mTOR) signalling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Crotonylome proteomics was performed in peripheral blood mononuclear cells from patients with LN, patients with systemic lupus erythematosus without nephritis and healthy controls. Renal biopsy tissues were evaluated for tubulointerstitial fibrosis and autophagy\u2013lysosome pathway-related markers. Mechanistic studies were conducted in lipopolysaccharide-stimulated HK-2 cells. Autophagic flux was assessed using bafilomycin A1. The dependency of mTOR\/autophagy changes on RAB1A was tested by siRNA-mediated knockdown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>MLKL was identified as a differentially crotonylated protein in LN, with increased crotonylation at K95 and K219. Kidney tissues from patients with LN showed increased fibronectin and collagen III deposition compared with controls, whereas no significant difference was observed between class IV and class V LN. LC3 signal did not differ significantly between groups, whereas LAMP1 expression and LC3\u2013LAMP1 co-localisation were reduced in LN. In HK-2 cells, crotonylation-deficient MLKL mutants were associated with increased LC3-II and reduced p62, whereas K219Q showed the opposite pattern. Autophagic flux assays using bafilomycin A1 showed that K219R-expressing cells had higher LC3-II levels than WT cells both before and after lysosomal inhibition, with comparable BafA1-induced LC3-II accumulation, consistent with increased autophagosome formation rather than impaired lysosomal degradation. HDAC1 knockdown increased MLKL crotonylation and was accompanied by mTOR activation. MLKL crotonylation enhanced RAB1A guanriphosphat osphate (GTP) binding without altering total RAB1A abundance. RAB1A knockdown in MLKL WT-expressing cells attenuated mTOR phosphorylation and partly reversed the autophagy-suppressive marker profile. Sodium crotonate induced an autophagy-suppressive marker profile that was partly reversed by rapamycin.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>MLKL crotonylation is associated with activation of the RAB1A\u2013mTOR axis and altered tubular autophagy\u2013lysosome pathway homeostasis in LN. These findings suggest that tubular injury-related changes in LN may not be fully reflected by glomerulus-based classification alone.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/lupus-2026-002116","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T12:30:16Z","timestamp":1788179416000},"page":"e002116","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Crotonylome profiling identifies MLKL crotonylation in lupus nephritis associated with RAB1A\u2013mTOR signalling and autophagy changes in tubular epithelial cells"],"prefix":"10.1136","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5205-3636","authenticated-orcid":false,"given":"Rui-Ling","family":"Lu","sequence":"first","affiliation":[{"name":"Department of Rheumatology and Immunology, Shenzhen People\u2019s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu-Hui","family":"Meng","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Shenzhen People\u2019s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China"},{"name":"Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quan-Zhou","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Pathology, Shenzhen People\u2019s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanran","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Shenzhen People\u2019s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xufa","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Shenzhen People\u2019s Hospital (The Second Clinical Medical College, Jinan University; 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