The Italian question was not settled with the complete defeat of the French at Pavia. The most powerful of the states, the papacy still stood between the imperial-spanish alliance. The battle of Pavia didn't immediately doom the papacy as Pope Clement VII who overstretched his forces in alliance with the French. The Colonna faction of the papacy forced a mediation with the newly coronated emperor: Albert III and would mediate the difference giving the emperor incredible power forcing down a compromise between the two factions. This would weaken the papacy considerably and Charles I would take advantage of this situation to finally remove the papacy from his new kingdom.
In 1526, the Kingdom of Naples, a de jure vassal of the Papacy was dissolved along with the Aragonese kingdom of Sicily due to Charles I of Spain wishing to completely remove any other ties to the papacy. Charles would begin to reorganize them as duchies which were under the Aragonese Crown. Through a usage of various of interesting legal wording and importantly through political will he had both kingdoms of Sicily dissolved triggering the papacy. Both of these kingdoms were technically a papal fief and the dissolvement of these kingdoms and assumption into the Crown of Aragon was practically a Declaration of Independence. Charles asserted that he was merely exercising the powers of the treaty of Madrid signed in 1526, however since the papacy was not actually participating in that treaty. Pope Clement VII saw it as treasonous, even worse was the execution of the treaty of Madrid for the Milanese who within the month agreed to the terms and recognized Albert III as heir if Francesco II had no male heirs. Francesco already was not entirely pleased with the imperial presence there along with the forced agreement of recognition and began to seek further allies.
Burgundy who had completely lost the war of danish succession and seeing the chaos that unfolded with the diet of worms and the Swabian Peasant's war saw Italy as an opportunity to further weaken the imperial line and reestablish the ancient Burgundian sphere of Italy that was not seen since the treaty of Moncelari in 1475. France under Henri's attempt at reconciliation with the French through the relatively light terms of the Treaty of Madrid would pay off as Francis, Richard and Henri would meet in Cambrai to sign a new peace and a triple alliance against the Imperial-Spanish alliance coalescing around Italy. This alliance however, would prove to be quite weak as all three parties were only putting aside their conflicts over Artois, Champagne and Calais in order to deny the Habsburgs-Trastamara alliance further power in Italy. This alliance would be further complicated due to the backroom negotiations between the three and the Habsburg-Trastamara. Burgundy was not entirely opposed to Spain seizing Naples as they saw it as impossible to maintain. They were very much steadfast in refusing Habsburg control of Milan however, as they wished to appoint their second son William as Duke of Milan which Francesco was not opposed to as gaining Burgundy as an ally had led Milan to prosper and his people were quite fond of the Burgundians seeing them as the last protectors of peace. France was opposed completely to the Spanish acquisition of Naples from them and wished to retake it especially considering Francis was the former king of Naples himself, he still had ambitions over Milan but he waited patiently to execute those plans. England would be the most unwilling to do so seeing the remarriage of Richard IV with Katherine of Aragon in particular kicking in doubt for the king. Importantly to England, the majority of these talks were under the impression to further boost English prestige and they had no reasons or qualms to war against the Spanish.
The nail in the coffin of this doomed alliance would be the inclusion of Venice joining in this league. Albert III was now quite eager to win glory for himself, and assembled his imperial army with the imperial diet of 1526 in Nuremberg he repealed the edict of worms, giving the protestants more room to breathe and declared a new Italienzug to be coronated as emperor. This direct threat would pit the empire against the League of Cognac. England would leave the war immediately, officially due to a small pretension over the honours given to their king but in reality realizing the situation was hopeless. Henri for his part launched an attack on the protestants who at this point also were in Cologne, his elector and Munster a reformist bishop who betrayed the Burgundian cause. This war between the protestants and Burgundy would keep Henri busy as the various princes of the empire saw this as an attack and breaking of the diet of Worms in 1495. They would back the two bishoprics as Henri would lead his armies devastating Cologne and Munster. Albert III, played his cards close to his chest and launched an all out assault into Italy with the armies of Charles I of Spain heading to Rome from Naples.
The betrayal of Charles III of Bourbon who fled to Vienna to pledge his allegiance to Albert III in exchange for recognition for his title of Duke of Provence and the incorporation of the Bourbon lands into the Holy Roman Empire would set off Albert's Italienzug led by Charles who marched south defeated Venice and Milan in short succession which Francesco would flee to Burgundy to which the Burgundians would welcome him warmly and begin to rebuild a new army to invade Italy and liberate the duchy of Milan. Albert however, would continue gaining the allegiance and alliance of the duchy of Ferrara keen on dismantling the papacy. The devastating sack of Rome would forever taint the reputation of Albert III, who while saving the library of the Vatican after taking the city with a quick siege would imprison the pope and force him to negotiate a new peace that would further strengthen the imperial presence in Italy. Pope Clement VII for his genius would flee to Provence and later arrive at Burgundy disguised and arriving at the court of Nancy. Henri who at this point returned to Nancy after signing an insignificant peace with Cologne and Munster in which they agreed to principle to respect the fifth council of the latheran and to restore/revive catholic education would be shocked with the papacy arriving. The pope would finally give his approval to the annexation of various prince-bishoprics and the surrender of papal authority there, while Clement VII offered Henri a crown, instead Henri realizing this would ruin his position with the electors decided against it and pushed for various reformist ideals including an ecumenical council importantly he would gain a new privilege which would define Burgundy, the pragmatic sanction of Nancy. This was a new version of the pragmatic sanction of Bourges but for Burgundy, recognizing the current lands of Henri I the fortunate of Burgundy's clergy to answer to a crown cardinal that was directly subordinate to the pope, appeals would be subject first to a council in Nancy before being sent to the Roman curia with a minimum of 1/3 members of the roman curia and Burgundian council approving the appeal of the case, along with importantly the Duke of Burgundy being granted the right to appoint all candidates of the church to any position within Henri's holdings however, only with papal approval should those candidates gain their position. This pragmatic sanction was a heavy but recoverable blow to the papacy as similar deals were signed with France in 1516.
Burgundy would become a new centre of renaissance after the sack and most if not all historians agree that this sack either triggered or was the last possible start date for the Burgundian renaissance as Italian artists, and thinkers fled to Burgundy where the pope was and where Henri would freely sponsor this type of renaissance. The imprisonment and later escape of Clement would also produce some various consequences, the papacy was now ordered to produce a new general council to deal with the issues of Lutheran thought, Albert would be crowned emperor as well, forcefully and quickly with the imprisoned Clement and marched back north to deal with the French. The complete collapse to the Medici in Florence would further strengthen the position of the Trastamara as well, with Charles I of Spain eagerly during the imprisonment of Clement force him to recognize the collapse of the two kingdoms of Sicily, and agreed to the recognition of the local nobility who reformed a now Second Kingdom of Sicily for Charles I of Spain who was now crowned by himself Charles IV of Sicily.
Richard IV who at this point was furious over the sack of Rome immediately pledged his forces with France and went to war against the Spanish-Habsburg alliance. The combined armies of Burgundy, England and France would arrive shortly afterwards in Milan to face off against Albert himself who led his combined Imperial-Spanish armies. This decisive victory for the League of Cognac would lead to two separate wars, Burgundy marched east head towards Austria in the hopes of crushing and driving out imperial influence once and for all. Francis I of France marched south to Naples to face off against Charles I of Spain and Sicily to finally reconquer the dissolved kingdom of Naples. England however would march to Rome to liberate and restore the papacy back to Rome. Unfortunately the betrayal of Genoa, who was always a reluctant ally of the League would doom this triple effort of bringing back the status quo. The shattering of the French armies in Naples would force Francis to retreat, Clement who just recently returned to Rome surrendered to Charles and Albert while Burgundy would fight a slow retreat back into Vaud and Aosta. This decisive defeat would force a new treaty this time in Cambrai in which the treaty of Madrid was recognized but with only minor changes, the recognition of the pragmatic sanction of Nancy, and importantly for Milan and Burgundy the recognition of Francesco II as Duke of Milan instead of the outright conquest that Albert tried to do, delaying the annexation of Milan by the Habsburgs for another couple of years.
This abandonment of England, France and Burgundy would leave the papacy to surrender recoronating Albert III as emperor this time with a proper ceremony and proof that this wasn't forced as some princes believed. Clement would be forced to absolve the participants of the sack of Rome and would gain minor territories from Venice as compensation. The real losers in this war was Venice and Florence who were stripped of their territories in Naples, and Austria would annex various parts of Venice as well. Florence would fall and be restored as the duchy of Florence with Alessandro d'Medici as duke. The complete abandonment by the pope would force him to be subservient to both the Spanish and the Habsburgs trying to push for a stricter policy against the protestants but once again avoiding both Burgundian and Imperial pressure for another general council against the Lutherans. Importantly for Burgundy and secretly, the papacy agreed to dissolve the Kingdom of Burgundy/Arles from a papal viewpoint as it was officially defunct and agreed if the emperor would approve the dissolvement of the kingdom they would approve and pressure the imperial to elevate Henri as King of Burgundy, this would set the nearly two century long struggle for the creation of the fourth kingdom of Burgundy. What was genuinely real however, was the proclamation of the pragmatic sanction of Nancy which consolidated the church in Burgundy under the crown cardinal: Erasmus, which would inevitably allow greater effort exerted for the Burgundian counter-reformation and also importantly proved a point in anti-clericalism which while would not be used by the princes for nearly two centuries would be the keystone to the German mediatisation.