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Peptidyl\u2010prolyl cis\u2010trans isomerase A (PPIA) interacts with TDP\u201043 and influences its aggregation and function. This interaction is facilitated by PPIA Lys\u2010acetylation. Here, we investigated whether restoring lysine acetylation homeostasis exerts protective effects on TDP\u201043 proteinopathy in\u00a0vitro and in\u00a0vivo and how this relates with PPIA. We found that vorinostat\/SAHA, a broad\u2010spectrum histone deacetylase (HDAC) inhibitor that increases PPIA acetylation, is able to reverse TDP\u201043 mislocalization in a cellular model of TDP\u201043 proteinopathy. We confirmed its effects in peripheral blood mononuclear cells from ALS patients and explored its impact on TDP\u201043 proteinopathy and PPIA acetylation in the Thy1\u2010hTDP\u201043 mouse model. Thy1\u2010hTDP\u201043 mice treated with SAHA showed a delayed onset of TDP\u201043 pathology, associated with PPIA nucleus\u2010cytoplasm redistribution, lower neurodegeneration and neuroinflammation, and improved neuromuscular function markers. However, these effects were transient. When combined with arimoclomol, a heat shock protein co\u2010inducer, a mitigation of the neurodegeneration was sustained. A synergistic effect was observed in periphery, greatly enhancing tubulin acetylation and reducing phosphorylated TDP\u201043 accumulation in the sciatic nerve and acetylcholine receptor \u03b3\u2010subunit expression in gastrocnemius muscle. This study suggests that HDAC inhibition could be beneficial in restoring TDP\u201043 localization and function through multiple mechanisms, including modulation of PPIA acetylation. The combination of lysine deacetylation inhibition and arimoclomol shows a synergistic effect in\u00a0vivo and has potential as a therapeutic approach for patients.<\/jats:p>\n                  <jats:p>\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70493-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.70493","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T10:25:21Z","timestamp":1781259921000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Effects of Lysine Deacetylation Inhibition Alone or in Combination With Arimoclomol on\n                    <scp>TDP<\/scp>\n                    \u201043 Proteinopathy"],"prefix":"10.1111","volume":"170","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-5525-0951","authenticated-orcid":false,"given":"Serena","family":"Scozzari","sequence":"first","affiliation":[{"name":"Research Center for ALS Istituto di Ricerche Farmacologiche Mario Negri IRCCS  Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano Fabrizio","family":"Columbro","sequence":"additional","affiliation":[{"name":"Research Center for ALS Istituto di Ricerche Farmacologiche Mario Negri IRCCS  Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Favagrossa","sequence":"additional","affiliation":[{"name":"Research Center for ALS Istituto di Ricerche Farmacologiche Mario Negri IRCCS  Milano 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